OBJECTIVES To explore mechanisms whereby hepatic steatosis may be associated with cardiovascular risk, we investigated cross-sectional relationships between hepatic steatosis, regional fat accumulation, inflammatory biomarkers, and subclinical measures of atherosclerosis in the Diabetes Heart Study. METHODS The Diabetes Heart Study is a family study of sibling pairs concordant for type 2 diabetes. A subset of 623 randomly selected participants was evaluated for hepatic steatosis, defined as a liver:spleen attenuation ratio of <1.0 by computed tomography. We quantified visceral fat, subcutaneous fat, coronary, aortic, and carotid artery calcium by computed tomography; and carotid atherosclerosis by ultrasound. Associations between the liver:spleen attenuation ratio and these factors were expressed as Spearman correlations. RESULTS After adjustment for age, race, gender, body mass index, and diabetes status, the liver:spleen attenuation ratio correlated with visceral fat (r = −0.22, P < 0.0001) and subcutaneous fat (r = −0.13, P = 0.031). Hepatic steatosis was associated with lower high-density lipoprotein (r = 0.21, P < 0.0001), higher triglycerides (r = −0.25, P < 0.0001), higher C-reactive protein (r = −0.095, P = 0.004), and lower serum adiponectin (r = 0.34, P < 0.0001). There were no significant associations between the liver:spleen attenuation ratio and coronary, aortic, or carotid calcium, or carotid intimal thickness. CONCLUSIONS This suggests that hepatic steatosis is less likely a direct mediator of cardiovascular disease and may best be described as an epiphenomenon. The strong correlations between pro-atherogenic biomarkers, visceral fat, and elements of the metabolic syndrome suggest that hepatic steatosis reflects more than general adiposity, but represents a systemic, inflammatory, pro-atherogenic adipose state.
Background Muscadine grape seeds have high concentrations of polyphenolic compounds with antioxidant and other properties that would be expected to have favorable effects on endothelial function. Objectives To evaluate the effect of muscadine grape seed supplementation on endothelial function and cardiovascular risk factors in subjects with increased cardiovascular risk. Design In a randomized, double-blind, placebo-controlled crossover trial, 50 adults with coronary disease or ≥1 cardiac risk factor received muscadine grape seed supplementation (1300 mg daily) and placebo for 4 weeks each, with a 4-week washout. Resting brachial diameter and brachial flow-mediated dilation (FMD) and biomarkers of inflammation, lipid peroxidation, and antioxidant capacity were determined at the beginning and end of each period and compared in mixed linear models. Results There was no evidence of improved FMD (% change) with muscadine grape seed (muscadine grape seed: pre 5.2% ± 0.3%, post 4.6% ± 0.3%, p = 0.06; placebo: pre 5.3% ± 0.4%, post 5.2% ± 0.4%, p = 0.82; p for muscadine grape seed vs. placebo = 0.25). However, there was a significant increase in baseline diameter (mm) with muscadine grape seed supplementation (muscadine grape seed: pre 4.05 ± 0.09, post 4.23 ± 0.10, p = 0.002; placebo: pre 4.12 ± 0.11, post 4.12 ± 0.10, p = 0.93; p for muscadine grape seed vs. placebo = 0.026). All other biomarkers were not significantly altered by muscadine grape seed supplementation. Conclusions Four weeks of muscadine grape seed supplementation in subjects with increased cardiovascular risk did not produce a statistically significant increase in brachial flow-mediated vasodilation or a significant change in other biomarkers of inflammation, lipid peroxidation, or antioxidant capacity. However, the muscadine grape seed supplement did result in a significant increase in resting brachial diameter. The clinical significance of the effect on resting diameter is not yet established. More research is warranted to fully characterize the vascular effects of this and other grape-derived nutritional supplements and to determine whether these vascular effects translate into important clinical benefits.
Significantly different reasons for exclusion of LKD exist between potential Caucasian and AA LKD, particularly among women. Among the differences that we observed are potentially modifiable barriers to donation including obesity and failure to complete the donor evaluation. A further understanding of these barriers may help point to strategies for more effective recruitment and successful LKD.
Human tissue transglutaminase (TGM2) is a calcium-dependent crosslinking enzyme involved in the post-translational modification of intra- and extra-cellular proteins and involved in several neurodegenerative diseases. To find specific inhibitors to TGM2, two structurally diverse chemical libraries (Lopac and Prestwick) were screened. We found that ZM39923, a Janus kinase inhibitor and its metabolite ZM449829 were the most potent inhibitors with IC50 of 10 and 5 nM, respectively. In addition, two other inhibitors including Tyrphostin 47 and Vitamin K3 were found to have an IC50 in the µM range. These agents utilized in part a thiol-dependent mechanism to inhibit TGM2, consistent with the activation of TGM2 by reduction of an intra-molecular disulfide bond. These inhibitors were tested in a polyglutamine-expressing Drosophila model of neurodegeneration and found to improve survival. The TGM2 inhibitors we discovered may serve as valuable lead compounds for the development of orally active TGM2 inhibitors to treat human diseases.
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