ABSTRACT
We found a novel blue cyanine dye that exhibits negative photochromism. Upon photoexcitation of the dye solution, the blue colour visibly disappeared, and after several hours the absorbance of the solution recovered completely, indicating that the dye has high stability.
ABSTRACT
Recent data have shown that TLR4 performs a key role in cerebral ischemia-reperfusion injury which serves as the origin of the immunological inflammatory reactions. However, the therapeutic effects of pharmacological inhibitions of TLR4 and its immediate down-stream pathway remain to be uncovered. In the present study, on mice, intracerebroventricular injection of resatorvid (TLR4 signal inhibitor; 0.01 µg) significantly reduced infarct volume and improved neurological score after middle cerebral artery occlusion and reperfusion. The levels of phospho-p38, nuclear factor-kappa B, and matrix metalloproteinase 9 expressions were significantly suppressed in the resatorvid-treated group. In addition, NOX4 associates with TLR4 after cerebral ischemia-reperfusion seen in mice and human. Genetic and pharmacological inhibitions of TLR4 each reduced NOX4 expression, leading to suppression of oxidative/nitrative stress and of neuronal apoptosis. These data suggest that resatorvid has potential as a therapeutic agent for stroke since it inhibits TLR4-NOX4 signaling which may be the predominant causal pathway.
Subject(s)
Brain Ischemia/drug therapy , Brain Ischemia/metabolism , NADPH Oxidases/metabolism , Sulfonamides/pharmacology , Toll-Like Receptor 4/metabolism , Animals , Apoptosis/drug effects , Brain Ischemia/physiopathology , Case-Control Studies , Cell Death/drug effects , Disease Models, Animal , Female , Humans , Infarction, Middle Cerebral Artery/drug therapy , Male , Matrix Metalloproteinase 9/metabolism , Mice , Mice, Inbred Strains , Middle Aged , NADPH Oxidase 4 , NF-kappa B/metabolism , Neurons/drug effects , Neurons/metabolism , Neurons/pathology , Oxidative Stress/drug effects , Reactive Oxygen Species/metabolism , Reperfusion Injury/prevention & control , Signal Transduction/drug effects , Young AdultABSTRACT
The tumor microenvironment is characterized by hypoxia, low-nutrient levels, and acidosis. A natural product chemistry-based approach was used to discover small molecules that modulate adaptive responses to a hypoxic microenvironment through the hypoxia-inducible factor (HIF)-1 signaling pathways. Five compounds, such as baccharin (3), beturetol (4), kaempferide (5), isosakuranetin (6), and drupanin (9), that modulate HIF-1-dependent luciferase activity were identified from Brazilian green propolis using reporter assay. Compounds 3, 9 and 5 reduced HIF-1-dependent luciferase activity. The cinnamic acid derivatives 3 and 9 significantly inhibited expression of the HIF-1α protein and HIF-1 downstream target genes such as glucose transporter 1, hexokinase 2, and vascular endothelial growth factor A. They also exhibited significant anti-angiogenic effects in the chick chorioallantoic membrane (CAM) assay at doses of 300 ng/CAM. On the other hand, flavonoids 4 and 6 induced HIF-1-dependent luciferase activity and expression of HIF-1 target genes under hypoxia. The contents (g/100g extract) of the HIF-1-modulating compounds in whole propolis ethanol extracts were also determined based on liquid chromatography-electrospray ionization mass spectrometry as 1.6 (3), 14.2 (4), 4.0 (5), 0.7 (6), and 0.7 (9), respectively. These small molecules screened from Brazilian green propolis may be useful as lead compounds for the development of novel therapies against ischemic cardiovascular disease and cancer based on their ability to induce or inhibit HIF-1 activity, respectively.
Subject(s)
Biological Products/pharmacology , Hypoxia-Inducible Factor 1/antagonists & inhibitors , Propolis/chemistry , Biological Products/chemistry , Biological Products/isolation & purification , Brazil , Cell Survival/drug effects , Dose-Response Relationship, Drug , HEK293 Cells , Humans , Hypoxia-Inducible Factor 1/genetics , Hypoxia-Inducible Factor 1/metabolism , Molecular Conformation , Signal Transduction/drug effects , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Retinal angiogenesis is a leading cause of blindness, including retinopathy of prematurity, diabetic retinopathy, and age-related macular degeneration. Vascular endothelial growth factor (VEGF) is one of the major angiogenesis factors, and induces endothelial cell proliferation and migration. VEGF stimulates NADPH oxidase to produce reactive oxygen species (ROS), and ROS induce the transcription factors and genes involved in angiogenesis. In the present study, we demonstrated that GPU-4, 5-arylidene-2,4-thiazolidinedione derivative, demonstrates anti-angiogenic activity regarding human retinal microvascular endothelial cells (HRMECs) and retinal neovascularization in a mouse model of retinopathy of prematurity. GPU-4 inhibited the VEGF-induced radicals, proliferation, and migration in HRMECs without a PPARγ-mediated effect. Furthermore, systemic administration of GPU-4 inhibited the development of retinal neovascularization in a murine oxygen-induced retinopathy model but did not exert revascularization of the capillary-free area, which shows normal physiological revascularization. These findings indicate that GPU-4 suppressed in vitro and in vivo retinal neovascularization partly by a radical scavenging effect, suggesting that GPU-4 might be a potential therapeutic agent candidate for proliferative diseases of the retinal vasculature.
