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The mechanism of action of 2-hydroxyoleic acid (2OHOA), a potent antitumor compound, has not yet been fully elucidated. Here, we show that human cancer cells have markedly lower levels of sphingomyelin (SM) than nontumor (MRC-5) cells. In this context, 2OHOA treatment strongly augments SM mass (4.6-fold), restoring the levels found in MRC-5 cells, while a loss of phosphatidylethanolamine and phosphatidylcholine is observed (57 and 30%, respectively). The increased SM mass was due to a rapid and highly specific activation of SM synthases (SMS). This effect appeared to be specific against cancer cells as it did not affect nontumor MRC-5 cells. Therefore, low SM levels are associated with the tumorigenic transformation that produces cancer cells. SM accumulation occurred at the plasma membrane and caused an increase in membrane global order and lipid raft packing in model membranes. These modifications would account for the observed alteration by 2OHOA in the localization of proteins involved in cell apoptosis (Fas receptor) or differentiation (Ras). Importantly, SMS inhibition by D609 diminished 2OHOA effect on cell cycle. Therefore, we propose that the regulation of SMS activity in tumor cells is a critical upstream event in 2OHOA antitumor mechanism, which also explains its specificity for cancer cells, its potency, and the lack of undesired side effects. Finally, the specific activation of SMS explains the ability of this compound to trigger cell cycle arrest, cell differentiation, and autophagy or apoptosis in cancer cells.
Background: Athletes may differ in their resting metabolic rate (RMR) from the general population. However, to estimate the RMR in athletes, prediction equations that have not been validated in athletes are often used. The purpose of this study was therefore to verify the applicability of commonly used RMR predictions for use in athletes. Methods: The RMR was measured by indirect calorimetry in 17 highly trained rowers and canoeists of the German national teams (BMI 24 +/- 2 kg/m(2), fat-free mass 69 +/- 15 kg). In addition, the RMR was predicted using Cunningham (CUN) and Harris-Benedict (HB) equations. A two-way repeated measures ANOVA was calculated to test for differences between predicted and measured RMR (alpha = 0.05). The root mean square percentage error (RMSPE) was calculated and the Bland-Altman procedure was used to quantify the bias for each prediction. Results: Prediction equations significantly underestimated the RMR in males (p < 0.001). The RMSPE was calculated to be 18.4% (CUN) and 20.9% (HB) in the entire group. The bias was 133 kcal/24 h for CUN and 202 kcal/24 h for HB. Conclusions: Predictions significantly underestimate the RMR in male heavyweight endurance athletes but not in females. In athletes with a high fat-free mass, prediction equations might therefore not be applicable to estimate energy requirements. Instead, measurement of the resting energy expenditure or specific prediction equations might be needed for the individual heavyweight athlete.
Biomarkers for the prediction of mortality and morbidity in patients with renal replacement therapy
(2011)
The mortality of end-stage renal disease (ESRD) patients on dialysis remains high despite great improvement of dialysis technologies in the past decades.
These patients die due to infectious diseases (mainly sepsis), cardiovascular diseases such as myocardial infarction, heart failure, stroke, and, in particular, sudden cardiac death. End stage renal disease is a complex condition, where the failure of kidney function is accompanied by numerous metabolic changes affecting almost all organ systems of the human body. Many of the biomarker characteristics of the individually affected organ systems have been associated with adverse outcomes. These biomarkers are different in patients with ESRD compared to the general population in the prediction of morbidity and mortality. Biomarker research in this field should aim to identify patients at risk for the different disease entities.
Traditional biomarkers such as CRP, BNP, and troponins as well as new biomarkers such as fetuin, CD 154, and relaxin were analyzed in patients on dialysis. We will include observational as well as prospective clinical trials in this review. Furthermore, we will also discuss proteomics biomarker studies. The article assess the potential diagnostic value of different biomarkers in daily clinical practice as well as their usefulness for clinical drug development in end stage renal disease patients.
Background: Uremic cardiomyopathy contributes substantially to mortality in chronic kidney disease (CKD) patients. Glucagon-like peptide-1 (GLP-1) may improve cardiac function, but is mainly degraded by dipeptidyl peptidase-4 (DPP-4).
Methodology/Principal Findings: In a rat model of chronic renal failure, 5/6-nephrectomized [5/6N] rats were treated orally with DPP-4 inhibitors (linagliptin, sitagliptin, alogliptin) or placebo once daily for 4 days from 8 weeks after surgery, to identify the most appropriate treatment for cardiac dysfunction associated with CKD. Linagliptin showed no significant change in blood level AUC(0-infinity) in 5/6N rats, but sitagliptin and alogliptin had significantly higher AUC(0-infinity) values; 41% and 28% (p=0.0001 and p=0.0324), respectively. No correlation of markers of renal tubular and glomerular function with AUC was observed for linagliptin, which required no dose adjustment in uremic rats. Linagliptin 7 mu mol/kg caused a 2-fold increase in GLP-1 (AUC 201.0 ng/l*h) in 5/6N rats compared with sham-treated rats (AUC 108.6 ng/l*h) (p=0.01). The mRNA levels of heart tissue fibrosis markers were all significantly increased in 5/6N vs control rats and reduced/normalized by linagliptin.
Conclusions/Significance: DPP-4 inhibition increases plasma GLP-1 levels, particularly in uremia, and reduces expression of cardiac mRNA levels of matrix proteins and B-type natriuretic peptides (BNP). Linagliptin may offer a unique approach for treating uremic cardiomyopathy in CKD patients, with no need for dose-adjustment.
High vitamin A ingestion or high serum retinol have been postulated to increase the risk of fractures and osteoporosis by reduced bone mineral density (BMD). Retinol is carried and transported to the tissues bound to retinol binding protein 4 (RBP4) and transthyretin (TTR). The relationships between retinol, retinol transport protein, retinol binding protein 4 (RBP4) and transthyretin (TTR) and BMD and osteoporosis are unclear. To examine the association between retinol and RBP4 and TTR and osteoporosis, 73 osteoporotic and 71 normal Thai postmenopausal women were studied. RBP4 and retinol levels did not differ between the groups. Serum TTR was significantly higher in control than osteoporotic subjects (89.47 and 144.53 mu g/ml, respectively, p=0.003, Mann-Whitney U test). TTR was positively correlated with BMD at several sites, such as the total radius bone (r=0.172, p=0.008, Spearman rank test). Osteoporosis risk was analyzed with binary logistic regression. Lean elderly Thais with lower TTR levels had a higher risk of osteoporosis. RBP4 and retinol levels had no relationship with disease status among Thai post-menopausal women. These results suggest calcium, minerals, vitamins and the retinol transport protein, transthyretin may be involved in the pathogenesis of osteoporosis.
Fusarium spp. infection of cereal grain is a common problem, which leads to a dramatic loss of grain quality. The aim of the present study was to investigate the effect of Fusarium infection on the wheat storage protein gluten and its fractions, the gliadins and glutenins, in an in vitro model system. Gluten proteins were digested by F. graminearum proteases for 2, 4, 8 and 24 h, separated by Osborne fractionation and characterised by chromatographic (RP-HPLC) and electrophoretic analysis (SDS-Page). Gluten digestion by F. graminearum proteases showed in comparison with gliadins a preference for the glutenins whereas the HMW subfraction was at most affected. In comparison with a untreated control, the HMW subfraction was degraded of about 97% after 4 h incubation with Fusarium proteases. Separate digestion of gliadin and glutenin underlined the preference for HMW-GS. Analogue to the observed change in the gluten composition, the yield of the proteins extracted changed. A higher amount of glutenin fragments was found in the gliadin extraction solution after digestion and could mask a gliadin destruction at the same time. This observation can contribute to explain the frequently reported reduced glutenin amount parallel to an increase in gliadin quantity after Fusarium infection in grains.