Oxidative stress triggers cardiac fibrosis in the heart of diabetic rats.

Diabetic cardiomyopathy is characterized by myocyte loss and myocardial fibrosis, leading to decreased elasticity and impaired contractile function. The study examines the downstream signaling whereby oxidative stress, induced by hyperglycemia, leads to myocardial fibrosis and impaired contractile function in the left ventricle of diabetic rats. It also examines the effects of dehydroepiandrosterone (DHEA), which prevents the oxidative damage induced by hyperglycemia in experimental models. DHEA was administered for 6 wk in the diet [0.02%, wt/wt)] to rats with streptozotocin-induced diabetes. Oxidative balance, advanced glycated end products (AGEs) and AGE receptors, transcription factors nuclear factor-kappaB and activator protein-1, and profibrogenic growth factors (connective tissue growth factor and TGFbeta1) were determined in the left ventricle of treated and untreated streptozotocin-diabetic rats. Structural and ultrastructural changes, and the contractile force developed by electrically driven papillary muscles, under basal conditions and after stimulation with isoproterenol, were also evaluated. Oxidative stress induced by hyperglycemia increased AGEs and AGE receptors and triggered a cascade of signaling, eventually leading to interstitial fibrosis. DHEA treatment, by improving oxidative balance, counteracted the enhanced AGE receptor activation and increase of profibrogenic factors and restored tissue levels of collagen I, collagen IV, and fibronectin to those of control animals. Moreover, DHEA completely restored the contractility of isolated papillary muscle. Oxidative stress led to cardiac fibrosis, the most important pathogenetic factor of the heart's impaired functional integrity in diabetes. Structural and ultrastructural changes and impairment of muscle function induced by experimental diabetes were minimized by DHEA treatment.

Valproic acid is a selective antiproliferative agent in estrogen-sensitive breast cancer cells.

Treatment efficacy of breast cancer can be impaired by cell resistance. The aim of the study was to investigate the anti-tumour effects of valproic acid (VPA), the only clinically available histone deacetylase inhibitor, on both estrogen-sensitive and -insensitive breast cancer cells. VPA, at a concentration lacking severe adverse effects in human, reduces cell viability in estrogen-sensitive cell lines, inducing p21 expression and impairing cell cycle. In ZR-75-1, cell cycle is selectively arrested in G1, whereas MCF-7 cells massively accumulated in sub-G1. Actually, in MCF-7 cells, VPA induces apoptosis, down-regulates Bcl-2 and up-regulates Bak expression. In conclusion, VPA is a powerful antiproliferative agent in estrogen-sensitive breast cancer cells, making this drug of clinical interest as a new approach to treat breast cancer.

Oxidative stress-dependent impairment of cardiac-specific transcription factors in experimental diabetes.

Oxidative stress plays a key role in the pathogenesis of diabetic cardiomyopathy, which is characterized by myocyte loss and fibrosis, finally resulting in heart failure. The study looked at the downstream signaling whereby oxidative stress leads to reduced myocardial contractility in the left ventricle of diabetic rats and the effects of dehydroepiandrosterone (DHEA), which production is suppressed in the failing heart and prevents the oxidative damage induced by hyperglycemia in several experimental models. DHEA was given orally at a dose of 4 mg/rat per day for 21 d to rats with streptozotocin (STZ)-induced diabetes and genetic diabetic-fatty (ZDF) rats. Oxidative balance, advanced glycated end products (AGEs) and AGE receptors, cardiac myogenic factors, and myosin heavy-chain gene expression were determined in the left ventricle of treated and untreated STZ-diabetic rats and ZDF rats. Oxidative stress induced by chronic hyperglycemia increased AGE and AGE receptors and led to activation of the pleoitropic transcription factor nuclear factor-kappaB. Nuclear factor-kappaB activation triggered a cascade of signaling, which finally led to the switch in the cardiac myosin heavy-chain (MHC) gene expression from the alpha-MHC isoform to the beta-MHC isoform. DHEA treatment, by preventing the activation of the oxidative pathways induced by hyperglycemia, counteracted the enhanced AGE receptor activation in the heart of STZ-diabetic rats and ZDF rats and normalized downstream signaling, thus avoiding impairment of the cardiac myogenic factors, heart autonomic nervous system and neural crest derivatives (HAND) and myogenic enhancer factor-2, and the switch in MHC gene expression, which are the early events in diabetic cardiomyopathy.

AGEs/RAGE complex upregulates BACE1 via NF-κB pathway activation.

Although the pathogenesis of sporadic Alzheimer disease (AD) is not clearly understood, it is likely dependent on several age-related factors. Diabetes is a risk factor for AD, and multiple mechanisms connecting the 2 diseases have been proposed. Hyperglycemia enhances the formation of advanced glycation end products (AGEs) that result from the auto-oxidation of glucose and fructose. The interaction of AGEs with their receptor, named RAGE, elicits the formation of reactive oxygen species that are also believed to be an early event in AD pathology. To investigate a functional link between the disorders diabetes and AD, the effect of 2 AGEs, pentosidine and glyceraldehydes-derived pyridinium (GLAP), was studied on BACE1 expression both in vivo, in streptozotocin treated rats, and in vitro in differentiated neuroblastoma cells. We showed that pentosidine and GLAP were able to upregulate BACE1 expression through their binding with RAGE and the consequent activation of NF-κB. In addition, both pentosidine and GLAP were found to be increased in the brain in sporadic AD patients. Our findings demonstrate that activation of the AGEs/RAGE axis, by upregulating the key enzyme for amyloid-ß production, provides a pathologic link between diabetes mellitus and AD.

SREBP-1c in nonalcoholic fatty liver disease induced by Western-type high-fat diet plus fructose in rats.

This study concentrated on the initial events triggering the development of nonalcoholic fatty liver disease induced by a high-fat plus fructose (HF-F) diet and on the possibility of delaying nonalcoholic fatty liver disease progression by adding dehydroepiandrosterone (DHEA) to the diet. Sterol regulatory element binding protein-1c (SREBP-1c) activation plays a crucial role in the progression of nonalcoholic fatty liver disease induced by an HF-F diet. This study investigated the protective effects of DHEA, a compound of physiological origin with multitargeted antioxidant properties, against the induction of SREBP-1c and on liver insulin resistance in rats fed an HF-F diet, which mimics a typical unhealthy Western diet. An HF-F diet, fortified or not with DHEA (0.01%, w/w), was administered for 15 weeks to male Wistar rats. After HF-F the liver showed unbalanced oxidative status, fatty infiltration, hepatic insulin resistance, and inflammation. The addition of DHEA to the diet reduced both activation of oxidative-stress-dependent pathways and expression of SREBP-1c and partially restored the expression of liver X-activated receptor-alpha and insulin receptor substrate-2 genes. DHEA supplementation of the HF-F diet reduced de novo lipogenesis and delayed progression of nonalcoholic fatty liver disease, demonstrating a relationship between oxidative stress and nonalcoholic fatty liver disease via SREBP-1c.