ABSTRACT
BACKGROUND: Vascular complications are major causes of disability and death in people with diabetes mellitus (DM). Nitric oxide (NO) supplement may help prevent vascular complications and is an attractive treatment option for DM. Hydroxytyrosol (HT) is a major polyphenol in olive oil. It is mainly used as a dietary supplement because of its antioxidant effect. PURPOSE: We aimed to determine the effects of hydroxytyrosol nitric oxide (HT-NO) on oxidative stress and NO level as well as related mechanisms. STUDY DESIGN/METHODS: The effects of HT-NO on oxidative stress and NO level were examined by using diabetic mouse model and HUVECs. RESULTS: Our results showed that HT-NO has antioxidant and NO-releasing activities in vitro and in DM mice. HT-NO not only decreased blood glucose and oxidative stress but also increased NO level and deacetylase Sirtuin 1 (SIRT1) expression in DM mice and high glucose (HG)-stimulated HUVECs. Further studies found that SIRT1 activation augmented the effect of HT-NO on eNOS phosphorylation in HG-stimulated HUVECs. However, the promotive effect of HT-NO on eNOS phosphorylation was abolished by SIRT1 knockdown. Most importantly, HT-NO inhibited reactive oxygen species (ROS) production through SIRT1 in HUVECs. The ROS scavenger enhanced the effect of HT-NO on eNOS phosphorylation. CONCLUSION: These results suggest that HT-NO regulates oxidative stress and NO production partly through SIRT1 in DM mice and HG-stimulated HUVECs.
Subject(s)
Diabetes Mellitus, Experimental/drug therapy , Human Umbilical Vein Endothelial Cells/drug effects , Nitric Oxide/metabolism , Oxidative Stress/drug effects , Phenylethyl Alcohol/analogs & derivatives , Sirtuin 1/metabolism , Animals , Antioxidants/pharmacology , Blood Glucose , Diabetes Mellitus, Experimental/metabolism , Dietary Supplements , Human Umbilical Vein Endothelial Cells/metabolism , Humans , Male , Mice , Nitric Oxide Synthase Type III/metabolism , Phenylethyl Alcohol/pharmacology , Phosphorylation , Rats, Sprague-Dawley , Reactive Oxygen Species/metabolism , Vasodilator Agents/pharmacologyABSTRACT
Nicotinic acid (NA) has recently been shown to inhibit inflammatory response in cardiovascular disease. Sirtuin1 (SIRT1), a NAD(+)-dependent class III histone deacetylase, participates in the regulation of cellular inflammation. We hypothesized that dietary supplementation of NA could attenuate vascular inflammation via modulation of SIRT1 pathway. New Zealand White rabbits received chow or chow supplemented with 0.6% (wt/wt) NA for 2 weeks. Acute vascular inflammation was induced in the animals by placing a non-occlusive silastic collar around the left common carotid artery. At 24 h after collar implantation, the collar-induced production of C-reactive protein and monocyte chemotactic protein-1 was significantly suppressed in the NA-supplemented animals. Meanwhile, NA also decreased the expression of cluster of differentiation 40 (CD40) and CD40 ligand, but up-regulated SIRT1 expression, both in rabbits and in lipopolysaccharide-stimulated endothelial cells. Moreover, knockdown of SIRT1 reversed the inhibitory effect of NA on CD40 expression. Further study revealed that NA also decreased the expression of CD40 partly through mammalian target of rapamycin. These results indicate that NA protects against vascular inflammation via the SIRT1/CD40-dependent signaling pathway.
Subject(s)
Niacin/pharmacology , Sirtuin 1/metabolism , Vasculitis/drug therapy , Vasculitis/metabolism , Animals , CD40 Antigens/genetics , CD40 Antigens/metabolism , Human Umbilical Vein Endothelial Cells/drug effects , Human Umbilical Vein Endothelial Cells/metabolism , Interleukin-1beta/blood , Lipids/blood , Lipopolysaccharides/pharmacology , Male , Rabbits , Signal Transduction/drug effects , Sirtuin 1/genetics , TOR Serine-Threonine Kinases/metabolismABSTRACT
Hydroxysafflor yellow A (HSYA), the main active natural constituent extracted from Carthamus tinctorius L., has been widely used for the treatment of cerebrovascular and cardiovascular diseases. The aim of this study is to explore the effect of HSYA on alcohol-induced liver injury and the underlying mechanism. Male Sprague-Dawley rats were used to establish the liver injury model induced by alcohol. HSYA treatment ameliorated serum biochemical indicators by reducing the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), hyaluronan (HA), laminin (LN), and type III precollagen (III-C) in rats. HSYA efficiently increased the activity and messenger RNA (mRNA) of superoxide dismutase (SOD) and glutathione peroxidase (GPx) in rat liver tissue compared with those of model group, which was obviously reduced by alcohol. HSYA also apparently decreased the levels of reactive oxygen species (ROS) and malondialdehyde (MDA) in rat liver tissue compared with those of model group, which was obviously enhanced by alcohol. Histological studies demonstrated that HSYA substantially reduced the number of macro- and micro-vesicular steatosis, suppressed hepatic fibrogenesis and shrunk ballooning degeneration areas, ameliorated the severity of liver damage induced by long-term drinking, and finally improved the liver architecture. In addition, immunohistochemistry study indicated that the activation of transforming growth factor β1 (TGF-β1) stimulated by alcohol in rat liver tissue was significantly blocked by HSYA. Collectively, these data demonstrated that HSYA can effectively protect the liver of rats from long-term alcohol injury, which relates with the enhanced antioxidant capacity of liver tissues and inhibition of TGF-β1 expression