No abstract

Shikonin derivatives, which are the active components of the medicinal plant Lithospermum erythrorhizon, exhibit many biological effects including apoptosis induction through undefined mechanisms. We recently discovered that orphan nuclear receptor Nur77 migrates from the nucleus to the mitochondria, where it binds to Bcl-2 to induce apoptosis. Here, we report that certain shikonin derivatives could modulate the Nur77/Bcl-2 apoptotic pathway by increasing levels of Nur77 protein and promoting its mitochondrial targeting in cancer cells. Structural modification of acetylshikonin resulted in the identification of a derivative 5,8-diacetoxyl-6-(1 ¶-acetoxyl-4 ¶-methyl-3 ¶-pentenyl)-1,4-naphthaquinones (SK07) that exhibited improved efficacy and specificity in activating the pathway. Unlike other Nur77 modulators, shikonins increased the levels of Nur77 protein through their posttranscriptional regulation. The apoptotic effect of SK07 was impaired in Nur77 knockout cells and suppressed by cotreatment with leptomycin B that inhibited Nur77 cytoplasmic localization. Furthermore, SK07 induced apoptosis in cells expressing the COOH-terminal half of Nur77 protein but not its NH 2 -terminal region. Our data also showed that SK07-induced apoptosis was associated with a Bcl-2 conformational change and Bax activation. Together, our results show that certain shikonin derivatives act as modulators of the Nur77-mediated apoptotic pathway and identify a new shikonin-based lead that targets Nur77 for apoptosis induction. [Cancer Res 2008;68(21):8871-80]

Background: This retrospective study aimed to evaluate the significance of serum immunoglobulin A/ complement 3 (IgA/C3) ratio and glomerular C3 staining at the onset of disease for predicting progression of IgA nephropathy in children. Methods: A total of 41 children with IgA nephropathy were allocated to two groups according to proteinuria (proteinuria <50 mg/kg/day group and proteinuria ≥50 mg/kg/day group) to compare their clinical data. Receiver operating characteristic (ROC) curves were used to evaluate the optimal cutoff value of serum IgA/C3 ratio in two groups. According to the optimal cutoff value of serum IgA/C3 ratio and glomerular C3 staining, the children were divided into four groups: Group A (serum IgA/C3 ratio <2.025 and glomerular C3 staining <2.0); Group B (serum IgA/C3 ratio ≥2.025 and glomerular C3 staining <2.0); Group C (serum IgA/C3 ratio <2.025 and glomerular C3 staining ≥2.0); and Group D (serum IgA/C3 ratio ≥2.025 and glomerular C3 staining ≥2.0). Then, the risk factors [including proteinuria and glomerular filtration rate (GFR) and pathological findings] were compared in these 4 groups at onset of IgA nephropathy. Results: Serum IgA/C3 ratio in the proteinuria <50 mg/kg/day group was significantly higher compared to the proteinuria ≥50 mg/kg/day group (P<0.01). According to ROC curves, the optimal cutoff value for the IgA/C3 ratio was 2.025 in two groups. At onset of IgA nephropathy, patients with IgA/C3 ratio <2.025 were predicted with nephrotic range proteinuria. When glomerular C3 staining was at the same level (glomerular C3 staining <2.0), GFR was significantly lower in group B (serum IgA/C3 ratio ≥2.025) compared with group A (serum IgA/C3 ratio <2.025). When serum IgA/C3 ratio was at the same level (serum IgA/C3 ratio <2.025), GFR was significantly lower in group C (glomerular C3 staining ≥2.0) compared with group A (glomerular C3 staining <2.0). Pathological findings and MEST (Oxford classification of IgA nephropathy) scores did not differ among the 4 groups at onset of the disease. Conclusions: Serum IgA/C3 ratio and glomerular C3 staining may be useful markers of the progression of IgA nephropathy in children, but not good markers for pathological findings at the onset of disease.