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Siddique M.M.,University of Nottingham Malaysia Campus | Li Y.,IDI Heart and Diabetes Institute | Chaurasia B.,IDI Heart and Diabetes Institute | Kaddai V.A.,IDI Heart and Diabetes Institute | Summers S.A.,IDI Heart and Diabetes Institute
Journal of Biological Chemistry | Year: 2015

Sphingolipid synthesis involves a highly conserved biosynthetic pathway that produces fundamental precursors of complex sphingolipids. The final reaction involves the insertion of a double bond into dihydroceramides to generate the more abundant ceramides, which are converted to sphingomyelins and glucosylceramides/gangliosides by the addition of polar head groups. Although ceramides have long been known to mediate cellular stress responses, the dihydroceramides that are transiently produced during de novo sphingolipid synthesis were deemed inert. Evidence published in the last few years suggests that these dihydroceramides accumulate to a far greater extent in tissues than previously thought. Moreover, they have biological functions that are distinct and non-overlapping with those of the more prevalent ceramides. Roles are being uncovered in autophagy, hypoxia, and cellular proliferation, and the lipids are now implicated in the etiology, treatment, and/or diagnosis of diabetes, cancer, ischemia/ reperfusion injury, and neurodegenerative diseases. This minireview summarizes recent findings on this emerging class of bioactive lipids. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Ahimastos A.A.,IDI Heart and Diabetes Institute | Latouche C.,IDI Heart and Diabetes Institute | Natoli A.K.,IDI Heart and Diabetes Institute | Reddy-Luthmoodoo M.,IDI Heart and Diabetes Institute | And 2 more authors.
Circulation Research | Year: 2014

RATIONALE:: We recently reported that ramipril more than doubled maximum walking times in patients with peripheral artery disease with intermittent claudication. OBJECTIVE:: Our aim was to conduct exploratory analyses of the effects of ramipril therapy on circulating biomarkers of angiogenesis/ arteriogenesis, thrombosis, inflammation, and leukocyte adhesion in patients with intermittent claudication. METHODS AND RESULTS:: One hundred sixty-five patients with intermittent claudication (mean, 65.3 [SD, 6.7] years) were administered ramipril 10 mg per day (n=82) or matching placebo (n=83) for 24 weeks in a randomized, double-blind study. Plasma biomarkers of angiogenesis/arteriogenesis (vascular endothelial growth factor-A, fibroblast growth factor-2), thrombosis (D-dimer, von Willebrand factor, thrombin-antithrombin III), inflammation (high-sensitivity C-reactive protein, osteopontin), and leukocyte adhesion (soluble vascular cell adhesion molecule-1, soluble intracellular adhesion molecule-1) were measured at baseline and 24 weeks. Relative to placebo, ramipril was associated with increases in vascular endothelial growth factor-A by 38% (95% confidence interval [CI], 34%-42%) and fibroblast growth factor-2 by 64% (95% CI, 44-85%; P<0.001 for both), and reductions in D-dimer by 24% (95% CI,-30% to-18%), von Willebrand factor by 22% (95% CI,-35% to-9%), thrombin-antithrombin III by 16% (95% CI,-19% to-13%), high-sensitivity C-reactive protein by 13% (95% CI,-14% to-9%), osteopontin by 12% (95% CI,-14% to-10%), soluble vascular cell adhesion molecule-1 by 14% (95% CI,-18% to-10%), and soluble intracellular adhesion molecule-1 by 15% (95% CI,-17% to-13%; all P<0.001). With the exception of von Willebrand factor, all the above changes correlated significantly with the change in maximum walking time (P=0.02-0.001) in the group treated with ramipril. CONCLUSIONS:: Ramipril is associated with an increase in the biomarkers of angiogenesis/arteriogenesis and reduction in the markers of thrombosis, inflammation, and leukocyte adhesion. This study informs strategies to improve mobility in patients with intermittent claudication.

Plat J.,Maastricht University | Mackay D.,University of Manitoba | Baumgartner S.,Baker IDI Heart and Diabetes Institute | Clifton P.M.,University of Helsinki | And 42 more authors.
Atherosclerosis | Year: 2012

Abundant evidence over past decades shows that foods with added plant sterols and plant stanols lower serum LDL cholesterol concentrations. However, despite the overwhelming data, numerous scientific questions still remain. The objective of this paper is to summarize the considerations of 60 academic and industrial experts who participated in the scientific meeting in Maastricht, the Netherlands, on issues related to the health effects of plant sterols and plant stanols. The meeting participants discussed issues including efficacy profiling, heterogeneity in responsiveness, effects beyond LDL-C lowering, and food formulation aspects of plant sterol and stanol consumption. Furthermore, aspects related to the potential atherogenicity of elevated circulatory plant sterol concentrations were discussed. Until the potential atherogenicity of plant sterols is resolved, based on the results >200 clinical trials, the risk to benefit of plant sterol use is favorable. Evidence on these topics in plant sterol and plant stanol research was presented and used to reach consensus where possible. It was concluded that endpoint studies looking at plant sterol and plant stanol efficacy are needed, however, there was no clear opinion on the best marker and best design for such a study. Based on the current scientific evidence, plant sterols and plant stanols are recommended for use as dietary options to lower serum cholesterol. © 2012.

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