OBJECTIVE-Estradiol (E 2 ) is known to modulate insulin sensitivity and, consequently, glucose homeostasis. Resveratrol (RSV), an agonist of estrogen receptor (ER), has exerted antihyperglycemic effects in streptozotocin-induced type 1 diabetic rats in our previous study and was also shown to improve insulin resistance in other reports. However, it remains unknown whether activation of ER is involved in the metabolic effects of RSV via insulin-dependent and -independent mechanisms. RESEARCH DESIGN AND METHODS-MaleSprague-Dawley rats were given a high cholesterol-fructose (HCF) diet for 15 weeks and were treated with RSV for either 15 days or 15 weeks.RESULTS-Here, we show that RSV shifts the metabolic characteristics of rats on an HCF diet toward those of rats on a standard diet. RSV treatment increased insulin-stimulated wholebody glucose uptake and steady-state glucose uptake of soleus muscle and liver in HCF-fed rats as well as enhanced membrane trafficking activity of GLUT4 and increased phosphorylation of insulin receptor in insulin-resistant soleus muscles. Interestingly, the phosphorylated ER level in insulin-resistant soleus muscle was significantly elevated in rats with RSV treatment in both basal and euglycemic-hyperinsulinemic conditions. RSV exerted an insulin-like stimulatory effect on isolated soleus muscle, epididymal fat and hepatic tissue, and C2C12 myotubes. The RSV-stimulated glucose uptake in C2C12 myotubes was dependent on extracellular signal-related kinase/p38 (early phase, 1 h) and p38/phosphoinositide 3-kinase (late phase, 14 h) activation. Inhibition of ER abrogated RSV-induced glucose uptake in both early and late phases.CONCLUSIONS-Collectively, these results indicate that ER is a key regulator in RSV-stimulating insulin-dependent and -independent glucose uptake, which might account for the protective effects of RSV on diet-induced insulin resistance syndrome.

trans-Resveratrol (resveratrol) has been shown in several studies to significantly modulate biomarkers of bone metabolism. But, there is no direct evidence supporting its inhibitory effect towards bone loss. In the present study, effects of resveratrol on bone mineral density (BMD) and bone calcium content (BCC) were examined in the ovariectomized (OVX) rat model. Female Wistar rats were divided into four groups: SHAM group (sham-operated), OVX group (OVX control), OVX + ALD group (OVX and treated with 1.0 mg/kg of body weight of alendronate sodium), and OVX + RES group (OVX and treated with 0.7 mg/kg of body weight of resveratrol). Tested materials were given by gavage for 12 weeks after ovariectomy. Results showed that rats in the OVX, OVX + ALD, and OVX + RES groups had significantly higher body weights and feed efficiency than those in the SHAM group (P < .01). The OVX group had significantly lower femoral epiphysis BMD than the SHAM group, and epiphysis BMD in the OVX + ALD and OVX + RES groups was significantly greater than that in the OVX group (P < .05). However, the femoral midpoint BMD was not significantly different among the four groups. Additionally, animals in the OVX group had significantly lower BCC compared with the SHAM group, while the BCC of the OVX + ALD and OVX + RES groups was significantly higher than that of the OVX group (P < .05). These results indicated that resveratrol could increase epiphysis BMD and inhibit the decrease of femur BCC in OVX rats, suggesting that it could play a role in protecting against bone loss induced by estrogen deficiency.

Deng J-Y, Huang J-P, Lu L-S, Hung L-M. Impairment of cardiac insulin signaling and myocardial contractile performance in high cholesterol-fructose-fed rats. Am J Physiol Heart Circ Physiol 293: H978-H987, 2007. First published March 30, 2007; doi:10.1152/ajpheart.01002.2006.-Although insulin resistance is recognized as a potent and prevalent risk factor for coronary heart disease, less is known as to whether insulin resistance causes an altered cardiac phenotype independent of coronary atherosclerosis. In this study, we investigated the relationship between insulin resistance and cardiac contractile dysfunctions by generating a new insulin resistance animal model with rats on high cholesterol-fructose diet. Male Sprague-Dawley rats were given high cholesterol-fructose (HCF) diet for 15 wk; the rats developed insulin resistance syndrome characterized by elevated blood pressure, hyperlipidemia, hyperinsulinemia, impaired glucose tolerance, and insulin resistance. The results show that HCF induced insulin resistance not only in metabolicresponse tissues (i.e., liver and muscle) but also in the heart as well. Insulin-stimulated cardiac glucose uptake was significantly reduced after 15 wk of HCF feeding, and cardiac insulin resistance was associated with blunted Akt-mediated insulin signaling along with glucose transporter GLUT4 translocation. Basal fatty acid transporter FATP1 levels were increased in HCF rat hearts. The cardiac performance of the HCF rats exhibited a marked reduction in cardiac output, ejection fraction, stroke volume, and end-diastolic volume. It also showed decreases in left ventricular end-systolic elasticity, whereas the effective arterial elasticity was increased. In addition, the relaxation time constant of left ventricular pressure was prolonged in the HCF group. Overall, these results indicate that insulin resistance reduction of cardiac glucose uptake is associated with defects in insulin signaling. The cardiac metabolic alterations that impair contractile functions may lead to the development of cardiomyopathy.Akt; glucose transporter; cardiac dysfunction; high cholesterol-fructose diet; insulin resistance HEART DISEASE IS A LEADING CAUSE of death in diabetic patients (43), with coronary artery disease (CAD) and atherosclerosis being the primary reasons for increased incidence of cardiovascular dysfunction (43, 38). However, a predisposition to heart failure might also reflect the effects of underlying abnormalities in cardiac diastolic function that can be detected in asymptomatic patients with diabetes (13, 4). Several etiological factors have been put forward to explain why hyperglycemia and/or diabetes tends to lead to diabetic cardiomyopathy. The accumulation of connective tissues, insoluble collagens (1), and abnormalities of various proteins that regulate ion flux (specifically, intracellular calcium) (18), has been proposed as an explanation for left ventricular wall stiffness and contractile dysfunctions. Recently, was speculated that diabetic cardiomyopathy could also occur as ...

Chemo- and radiotherapy cause multiple forms of DNA damage and lead to the death of cancer cells. Inhibitors of the DNA damage response are candidate drugs for use in combination therapies to increase the efficacy of such treatments. In this study, we show that curcumin, a plant polyphenol, sensitizes budding yeast to DNA damage by counteracting the DNA damage response. Following DNA damage, the Mec1-dependent DNA damage checkpoint is inactivated and Rad52 recombinase is degraded by curcumin, which results in deficiencies in double-stand break repair. Additive effects on damage-induced apoptosis and the inhibition of damage-induced autophagy by curcumin were observed. Moreover, rpd3 mutants were found to mimic the curcumin-induced suppression of the DNA damage response. In contrast, hat1 mutants were resistant to DNA damage, and Rad52 degradation was impaired following curcumin treatment. These results indicate that the histone deacetylase inhibitor activity of curcumin is critical to DSB repair and DNA damage sensitivity.