ABSTRACT
Oxidative stress and apoptosis are the key factors that limit the hypothermic preservation time of donor hearts to within 4–6 h. The aim of this study was to investigate whether the histone deacetylase 3 (HDAC3) inhibitor RGFP966 could protect against cardiac injury induced by prolonged hypothermic preservation. Rat hearts were hypothermically preserved in Celsior solution with or without RGFP966 for 12 h followed by 60 min of reperfusion. Hemodynamic parameters during reperfusion were evaluated. The expression and phosphorylation levels of mammalian STE20-like kinase-1 (Mst1) and Yes-associated protein (YAP) were determined by western blotting. Cell apoptosis was measured by the terminal deoxynucleotidyl-transferase (TdT)-mediated dUTP nick-end labeling (TUNEL) method. Addition of RGFP966 in Celsior solution significantly inhibited cardiac dysfunction induced by hypothermic preservation. RGFP966 inhibited the hypothermic preservation-induced increase of the phosphorylated (p)-Mst1/Mst1 and p-YAP/YAP ratios, prevented a reduction in total YAP protein expression, and increased the nuclear YAP protein level. Verteporfin (VP), a small molecular inhibitor of YAP-transcriptional enhanced associate domain (TEAD) interaction, partially abolished the protective effect of RGFP966 on cardiac function, and reduced lactate dehydrogenase activity and malondialdehyde content. RGFP966 increased superoxide dismutase, catalase, and glutathione peroxidase gene and protein expression, which was abolished by VP. RGFP966 inhibited hypothermic preservation-induced overexpression of B-cell lymphoma protein 2 (Bcl-2)-associated X (Bax) and cleaved caspase-3, increased Bcl-2 mRNA and protein expression, and reduced cardiomyocyte apoptosis. The antioxidant and anti-apoptotic effects of RGFP966 were cancelled by VP. The results suggest that supplementation of Celsior solution with RGFP966 attenuated prolonged hypothermic preservation-induced cardiac dysfunction. The mechanism may involve inhibition of oxidative stress and apoptosis via inactivation of the YAP pathway.
ABSTRACT
The study was designed to explore the effects of HS060098 on activation of peroxisome proliferator-activated receptors (PPARα, γ and δ) and in the down-regulation of hyperlipidemia in golden hamster. Luciferase gene reporters of PPARα, PPARγ and PPARδ were constructed in HepG2 cells and the green fluorescent protein (GFP) was used as an internal reference. Transfected cells were then cultured with various concentrations of HS060098 for 24 h. The peroxisome proliferator-response element luciferase activity was determined by the dual-luciferase reporter gene assay system. To investigate the lipid-lowering effect of HS060098, hyperlipidemic golden hamsters fed by high-diet were administered orally with HS060098 through prophylactic and therapeutic approaches respectively. The levels of blood lipids such as total cholesterol (TC), triglyceride (TG), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C) and fat index in hamsters were evaluated. The results showed that HS060098 was a potent activator of PPAR δ with a good selectivity and the median effective concentration (EC 50) is 0.01 μmol·L-1, while no obvious PPARα and PPARγ activation was observed. In the golden hamster, oral administration of HS060098 (5, 10, 20 mg·kg-1·d-1) for 2 weeks, led to a significant decrease the concentrations of plasma TC, TG, LDL-C and fat index (PPPPδ agonist with a significant activity in the prevention and therapy of hyperlipemia in golden hamster.
ABSTRACT
Objective: To explore the effect of 1,25-dihydroxyvitamin D3 on the mast cell tryptase (MCT) in asthmatic guinea pigs. Methods: A total of 60 male or female healthy guinea pigs were randomly divided into control group (group A), asthmatic group (group B), and 1,25-dihydroxyvitamin D3 group (group C), with 20 cases in each group. To establish asthmatic guinea pig models, 1mL peanut oil was filled into stomach in the morning in group A and group B, and 1mL peanut oil with 1,25-dihydroxyvitamin D3 was filled into stomach in group C. Airway resistance (Re) of asthmatic guinea pigs was detected, and the bronchoalveolar lavage fluid (BALF) cells were counted. Lung tissue with HE and MCT immunohistochemical staining were used to observe the pathological changes in lung tissue and the distribution of MCT. Results: After injection of different concentration of acetylcholine chloride, the Re in group B and group C were increased significantly compared with group A (P<0.05); compared with group B, the Re in group C were decreased significantly (t=-5.385,-5.761,-6.184,-13.574, P<0.05); the total number of BALF cells and eosinophils were increased significantly in group B and C (t=19.618, 9.598, 10.854, 5.388, P<0.05); compared with group B, the total number of BALF cells and eosinophils in group C was decreased significantly (t=-5.555,-5.392, P<0.05); the number of tryptase positive cells in group B was increased significantly than that in group A (t=21.312, P<0.05), and in addition to the alveolar septum and submucosa, the cells were also distributed around blood vessels and outside the cells; the number of tryptase positive cells in group C was decreased significantly compared with group B, and the difference was statistically significant (t=5.043, P<0.05). Conclusions: After the asthmatic guinea pigs are treated with 1,25-dihydroxyvitamin D3, their BALF, Re, infiltration degree of inflammatory cells in the trachea and lung tissue and airway inflammatory reaction are reduced significantly. 1,25-dihydroxyvitamin D3 has a certain inhibiting effect on the activation of mast cells and the release of MCT granules.
ABSTRACT
A series of [1,3]dioxolo[4,5-f]isoindolone derivatives were designed, synthesized and evaluated as inhibitors of acetylcholinesterases (AChE). Furthermore, their effects on memory impairment of mice induced by scopolamine were investigated with step-through test. The results suggested that most of the target compounds exhibited potential inhibition on AChE with IC50 values at micromolar range. Compounds I1 (IC50 value of 0.086 μmol · L(-1)) and I2 (IC50 value of 0.080 μmol · L(-1)) showed the strongest AChE inhibitory activity, which are equipotent to donepezil (IC50 value of 0.094 μmol · L(-1)). Moreover, compounds I1-I4 could improve the memory impairment induced by scopolamine in mice.
Subject(s)
Animals , Mice , Cholinesterase Inhibitors , Chemistry , Dioxoles , Chemistry , Drug Design , Indans , Inhibitory Concentration 50 , Isoindoles , Chemistry , Memory Disorders , Drug Therapy , Piperidines , ScopolamineABSTRACT
OBJECTIVE@#To explore the effect of 1,25-dihydroxyvitamin D3 on the mast cell tryptase (MCT) in asthmatic guinea pigs.@*METHODS@#A total of 60 male or female healthy guinea pigs were randomly divided into control group (group A), asthmatic group (group B), and 1,25-dihydroxyvitamin D3 group (group C), with 20 cases in each group. To establish asthmatic guinea pig models, 1 mL peanut oil was filled into stomach in the morning in group A and group B, and 1 mL peanut oil with 1,25-dihydroxyvitamin D3 was filled into stomach in group C. Airway resistance (Re) of asthmatic guinea pigs was detected, and the bronchoalveolar lavage fluid (BALF) cells were counted. Lung tissue with HE and MCT immunohistochemical staining were used to observe the pathological changes in lung tissue and the distribution of MCT.@*RESULTS@#After injection of different concentration of acetylcholine chloride, the Re in group B and group C were increased significantly compared with group A (P < 0.05); compared with group B, the Re in group C were decreased significantly (t = -5.385, -5.761, -6.184, -13.574, P < 0.05); the total number of BALF cells and eosinophils were increased significantly in group B and C (t = 19.618, 9.598, 10.854, 5.388, P < 0.05); compared with group B, the total number of BALF cells and eosinophils in group C was decreased significantly (t = -5.555, -5.392, P < 0.05); the number of tryptase positive cells in group B was increased significantly than that in group A (t = 21.312, P < 0.05), and in addition to the alveolar septum and submucosa, the cells were also distributed around blood vessels and outside the cells; the number of tryptase positive cells in group C was decreased significantly compared with group B, and the difference was statistically significant (t = 5.043, P < 0.05).@*CONCLUSIONS@#After the asthmatic guinea pigs are treated with 1,25-dihydroxyvitamin D3, their BALF, Re, infiltration degree of inflammatory cells in the trachea and lung tissue and airway inflammatory reaction are reduced significantly. 1,25-dihydroxyvitamin D3 has a certain inhibiting effect on the activation of mast cells and the release of MCT granules.