Mesenchymal stem cell (MSC) administration is a promising adjuvant therapy to treat tissue injury. However, MSC survival after administration is often hampered by oxidative stress at the site of ...injury. Heme oxygenase (HO) generates the cytoprotective effector molecules biliverdin/bilirubin, carbon monoxide (CO) and iron/ferritin by breaking down heme. Since HO-activity mediates anti-apoptotic, anti-inflammatory, and anti-oxidative effects, we hypothesized that modulation of the HO-system affects MSC survival. Adipose-derived MSCs (ASCs) from wild type (WT) and HO-2 knockout (KO) mice were isolated and characterized with respect to ASC marker expression. In order to analyze potential modulatory effects of the HO-system on ASC survival, WT and HO-2 KO ASCs were pre-treated with HO-activity modulators, or downstream effector molecules biliverdin, bilirubin, and CO before co-exposure of ASCs to a toxic dose of H sub(2)O sub(2). Surprisingly, sensitivity to H sub(2)O sub(2)-mediated cell death was similar in WT and HO-2 KO ASCs. However, pre-induction of HO-1 expression using curcumin increased ASC survival after H sub(2)O sub(2) exposure in both WT and HO-2 KO ASCs. Simultaneous inhibition of HO-activity resulted in loss of curcumin-mediated protection. Co-treatment with glutathione precursor N-Acetylcysteine promoted ASC survival. However, co-incubation with HO-effector molecules bilirubin and biliverdin did not rescue from H sub(2)O sub(2)-mediated cell death, whereas co-exposure to CO-releasing molecules-2 (CORM-2) significantly increased cell survival, independently from HO-2 expression. Summarizing, our results show that curcumin protects via an HO-1 dependent mechanism against H sub(2)O sub(2)-mediated apoptosis, and likely through the generation of CO. HO-1 pre-induction or administration of CORMs may thus form an attractive strategy to improve MSC therapy.
Objective
The guanine‐thymidine (GT)n repeat in the HMOX1 promoter determines the level of induction of the heme‐degrading enzyme heme oxygenase 1 (HO‐1), which protects against inflammatory and ...oxidative stress. In individuals with short (GT)n repeats (where n < 25; SS genotype), higher levels of HO‐1 activity are induced more rapidly than in those with long (GT)n repeats (where n ≥ 25; LL genotype). Recently, it was demonstrated that HO‐1 activity protects against the onset of rheumatoid arthritis (RA). The aim of this study was to determine whether the (GT)n‐repeat length within the HMOX1 promoter region is associated with RA disease severity and radiographic joint damage.
Methods
A cohort of 325 well‐characterized RA patients and 273 controls was investigated by DNA fragment‐length analysis for the association of (GT)n repeats in the HMOX1 promoter region with RA disease susceptibility and severity.
Results
Although no significant differences in genotype or allele frequency were found between controls and RA patients, the odds ratios corresponded well to those in the previously described cohort. Among patients, those carrying the SS genotype had a more favorable radiographic outcome over 9 years than those carrying the LL genotype. This was unexpected since no differences in disease activity were found between the genotypes or alleles.
Conclusion
Patients with the SS genotype have a better long‐term radiographic outcome despite poor prognostic markers at baseline and despite disease activity at followup similar to that of patients with the LL genotype. This suggests that the HMOX1/HO‐1 system is involved in the uncoupling of disease activity and joint damage and may provide a novel target for the treatment of RA.
Although Burkitt lymphomas and follicular lymphomas both have features of germinal center B cells, they are biologically and clinically quite distinct. Here we performed whole-genome bisulfite, ...genome and transcriptome sequencing in 13 IG-MYC translocation-positive Burkitt lymphoma, nine BCL2 translocation-positive follicular lymphoma and four normal germinal center B cell samples. Comparison of Burkitt and follicular lymphoma samples showed differential methylation of intragenic regions that strongly correlated with expression of associated genes, for example, genes active in germinal center dark-zone and light-zone B cells. Integrative pathway analyses of regions differentially methylated in Burkitt and follicular lymphomas implicated DNA methylation as cooperating with somatic mutation of sphingosine phosphate signaling, as well as the TCF3-ID3 and SWI/SNF complexes, in a large fraction of Burkitt lymphomas. Taken together, our results demonstrate a tight connection between somatic mutation, DNA methylation and transcriptional control in key B cell pathways deregulated differentially in Burkitt lymphoma and other germinal center B cell lymphomas.
Although the median survival for patients with cystic fibrosis (CF) is 32.9 years, a small group of patients live much longer. We analyzed the genotype and phenotype of CF patients 40 years and older ...seen between 1992 and 2004 at the National Jewish Medical and Research Center (n = 55). These patients were divided into two groups according to age at diagnosis: an early diagnosis (ED) group, median age at diagnosis 2.0 years (range 0.1-15 years, n = 28), and a late diagnosis (LD) group, median age of diagnosis 48.8 years (range 24-72.8 years, n = 27). Consistent with the hypothesis that the CFTR genotype affects the age at diagnosis, CFTR DeltaF508 homozygous individuals were more common in the ED group. Although patients in the ED group were predominantly male, the majority of LD patients were female. Patients with CF diagnosed late had a significantly lower prevalence of pancreatic insufficiency and CF-related diabetes, and better lung function. Fewer patients in the LD groups were infected with Pseudomonas aeruginosa, whereas a greater percentage had cultures positive for nontuberculous mycobacteria. This is the largest cohort of older patients with CF described to date, and our findings indicate that patients diagnosed as adults differ distinctly from survivors of long-term CF diagnosed as children.
We conducted a double-blind, placebo-controlled, multicenter, randomized trial to test the hypothesis that 300 mg of tobramycin solution for inhalation administered twice daily for 28 days would be ...safe and result in a profound decrease in Pseudomonas aeruginosa (Pa) density from the lower airway of young children with cystic fibrosis. Ninety-eight subjects were to be randomized; however, the trial was stopped early because of evidence of a significant microbiological treatment effect. Twenty-one children under age 6 years were randomized (8 active; 13 placebo) and underwent bronchoalveolar lavage at baseline and on Day 28. There was a significant difference between treatment groups in the reduction in Pa density; no Pa was detected on Day 28 in 8 of 8 active group patients compared with 1 of 13 placebo group patients. We observed no differences between treatment groups for clinical indices, markers of inflammation, or incidence of adverse events. No abnormalities in serum creatinine or audiometry and no episodes of significant bronchospasm were observed in association with active treatment. We conclude that 28 days of tobramycin solution for inhalation of 300 mg twice daily is safe and effective for significant reduction of lower airway Pa density in young children with cystic fibrosis.
One way to enhance the impact of smoking health risk messages may be to tailor their content to individual difference factors such as need for cognition (NFC). In this study, we examined how NFC ...influenced responses to different smoking risk messages. Outcomes included knowledge, risk perceptions, and behavioral expectations related to quitting smoking.
We randomized 402 participants to one of 4 different risk message sets that were manipulated in terms of emotionality and framing in a 2x2 design: (1) factual gain-framed, (2) factual loss-framed, (3) emotional gain-framed, and (4) emotional loss-framed.
Statistically significant main effects emerged for NFC and emotionality. For certain risk perceptions, those with lower NFC reported greater perceived risk in response to emotional messages and lower risk in response to factual messages; those with higher NFC showed an opposite pattern. Similarly, those with lower NFC reported greater risk in response to gain-framed messages and lower risk in response to loss-framed messages; the opposite pattern emerged for those lower in NFC.
Findings highlight the importance of an individual difference variable in influencing the impact of different types of smoking risk messages.
NO pathway in CF and non-CF children Wooldridge, Jamie L.; Deutsch, Gail H.; Sontag, Marci K. ...
Pediatric pulmonology,
April 2004, Letnik:
37, Številka:
4
Journal Article
A sensor platform has been developed that is capable of both aerial and terrestrial locomotion, as well as transitioning between the two. The morphing micro air-land vehicle (MMALV) implements ...biological inspiration in both flying and walking. MMALV integrates the University of Florida's micro air vehicle (MAV) technology with the terrain mobility of Mini-Whegs/spl trade/. Fabricated of lightweight carbon fiber, the UF-MAV employs a flexible wing design to achieve improved stability over other MAVs of similar size. Mini-Whegs/spl trade/ employs the patented (pending) wheel leg running gear that makes the Whegs/spl trade/ and Mini-Whegs/spl trade/ line of robots fast, agile, and efficient. MMALV has a 30.5cm wingspan, and is 25.4cm long. Terrestrial locomotion is achieved using two independently controlled wheel legs, which are differentially actuated to perform turning. The vehicle successfully performs the transition from flight to walking. Furthermore, MMALV is capable of transitioning from terrestrial to aerial locomotion by walking off a structure of only 20 feet. A wing retraction mechanism improves the portability of the vehicle, as well as its terrestrial stealth and ability to enter small openings.
Fourteen derivatives of sparsomycin (1) were synthesized. Six of them were prepared following a novel synthetic route starting from the L-amino acid alanine. Some physicochemical properties, viz. ...lipophilicity and water solubility, of selected derivatives were measured. The biological activity was tested in vitro in cell-free protein synthesis inhibition assays, in bacterial and tumor cell growth inhibition assays, and in the L1210 leukemia in vivo model in mice. Also for selected drugs the acute toxicity in mice was determined. Ribosomes from both an eukaryotic and a prokaryotic organism were used in the protein synthesis inhibition systems. A linear correlation between the lipophilicity parameters measured was observed. Water solubility and drug toxicity in mice were found to be linearly correlated with lipophilicity. All the derivatives studied are more lipophilic than 1. The deshydroxysparsomycin analogues (30-33) showed an interesting phenomenon: increase in hydrophobicity was accompanied by a considerable increase in water solubility. We found that an increase in hydrophobicity of the drug as a result of replacing the SMe group of 1 with larger alkylthio groups causes an increase in the biological activity of the drug. However, not only the hydrophobicity but also shape and size of the substituent are important; in the homologous series 1-9-10-11-12, 21-22-23-24, and 30-31-32-33, highest protein synthesis inhibitory and in vitro cytostatic activity is found with compounds 11, 23, and 32, respectively, and in comparison with the highly active n-butyl compound 10, the isomeric tert-butyl compound 13 is rather inactive. Polar substituents replacing the SMe group, i.e. Cl in 17 and 35, also render the molecule inactive. Substituting the bivalent sulfur atom for a methylene group decreases the drug's activity. This effect can be compensated for by increasing the length of the alkylsulfinyl side chain. The agreement between the results derived from cell-free and "in vivo" tests is good. The assays using ribosomes of bacterial and eukaryotic organisms give similar results although the latter seem to be more sensitive to changes in hydrophobicity of the drug. Our results confirm the presence of a hydrophobic region at the peptidyl transferase center of the ribosome; the interaction of sparsomycin with this region is more pronounced in the eukaryotic particles. The sparsomycin analogues 11, 23, and 30 show the highest antitumor activity against L1210 leukemia in mice, their median T/C values are 386, 330, and 216%, respectively.
PDF
