Vuong N. Trieu

In vivo antioxidant activity of genistein in a murine model of singlet oxygen-induced cerebral stroke

We evaluated the in vivo antioxidant activity of genistein in a mouse model of singlet oxygen-induced cerebral stroke. Cerebral stroke was induced in male BALB/c mice through extensive microvessel damage caused by photoactivated rose bengal dye. The photoactivation of the intravenously administered rose bengal was achieved by transcranial illumination with green light. Genistein was more active than its analogs and other antioxidants that were used as control agents. At a dose of 16 mg/kg genistein administered every 6 h from 24 h prior to irradiation until 24 h after irradiation, the average size of the cerebral lesion of genistein-treated mice was significantly smaller than that in control mice treated with the carrier DMSO (8.1 +/- 1.0 mm(2) compared to 14.6 +/- 0.7 mm(2), P < 0.001). Our findings provide experimental evidence that genistein could be useful for the prevention of cerebral stroke and other pathological conditions caused by reactive oxygen species.

EGF-genistein inhibits neointimal hyperplasia after vascular injury in an experimental restenosis model.

A murine model of vascular injury-induced neointimal hyperplasia was developed by using a photoactive dye, rose bengal. Photoactivation of rose bengal induced vascular injury to the femoral arteries of C57B1/6 mice and resulted in an occlusive neointimal hyperplasia after 4 weeks. The cellular elements of the hyperplastic neointima were found to be alpha-actin-positive vascular smooth muscle cells expressing epidermal growth factor (EGF) receptor at high levels. EGF-Gen, an EGF-R-specific inhibitor with potent anticancer activity, suppressed the formation of hyperplastic neointima. Morphometric analysis of serial tissue sections at 4 weeks after vascular injury showed that in 75% of the EGF-Gen-treated mice, the maximal stenosis index was only 0.44 +/- 0.13, whereas in 75% of phosphate-buffered saline (PBS)-treated mice, the maximal stenosis index was 1.20 +/- 0.25. The mean neointima/media ratios for areas of maximum neointimal hyperplasia were 0.59 +/- 0.16 (n = 24) for the EGF-Gen-treated group, 0.99 +/- 16 (n = 45) for the PBS group (EGF-Gen vs. PBS, p = 0.0017), and 1.03 +/- 18 (n = 8) for group treated with unconjugated genistein (EGF-Gen vs. Gen, p = 0.0088). EGF-Gen treatment of mice with vascular injury to the left femoral artery was not associated with any clinical signs of toxicity or histopathologic lesions in any of the organs, including the uninjured right femoral artery. EGF-Gen also inhibited VSMC migration in vitro, without affecting VSMC proliferation and viability, suggesting that EGF-Gen is blocking neointima formation by inhibiting cellular migration to vascular injury sites. In conclusion, EGF-Gen may be useful as a nontoxic prophylactic agent for prevention of restenosis in clinical settings.

Triglyceride-rich lipoprotein interactions with Lp(a).

We found a significantly reduced incidence of increased lipoprotein(a) (Lp(a)) levels in subjects with triglycerides (TG) greater than 150 mg/dl compared with those with TG levels lower than 150 mg/dl. This was the case in patients with angiographically documented coronary artery disease (CAD) and in subjects with no CAD. We explored the potential role of lipoprotein lipase (LPL) in mediating this relationship. Lp(a) and LDL2 exhibited a minimal effect on the rate constant for degradation of VLDL-TG by LPL (13% inhibition). Binding analyses indicated no differences between VLDL and LDL with respect to Lp(a) binding, and lipolysis only reduced binding by 30% at 75% degradation of VLDL-TG. Our study indicates that the inverse relationship between elevated plasma TG and Lp(a) levels is not caused by activation of LPL by Lp(a) either due to failure of Lp(a) to bind to VLDL or its lipolytic remnants. It is hypothesized that this relationship could stem from the enhanced clearance of TG-rich lipoproteins in individuals with higher levels of Lp(a) by receptor-mediated events.