The antimutagenicity of 2-substituted selenazolidine-4-(R)-carboxylic acids

Selenium can have cancer chemopreventive activity, although the mechanism of action has not been well defined. Selenazolidine-4-(R)-carboxylic acids (SCAs) were devised as prodrugs of L-selenocysteine, to provide selenium in a form and at a concentration commensurate with cancer chemopreventive activity. In the present study, a series of selenazolidines has been evaluated in the Salmonella typhimurium TA98 tester strain and all were found to possess antimutagenic activity. There was little difference between the seven selenazolidines in their effectiveness against either benzo[a]pyrene (B[a]P) or 3,6-bis(dimethylamino)acridine (acridine orange), agents which differ in their requirement for mammalian enzyme bioactivation for mutagenicity. Antimutagenic activity against acridine orange was dependent on selenazolidine concentration, and EC50 values were in the 5-10 microM range. At 25 microM, the concentration tested in common for the two mutagens, the selenazolidines were more effective antimutagens against acridine orange than against B[a]P, with reductions in mutant frequency ranging from 54 to 71% for B[a]P and 79 to 93% for acridine orange. Efficacy against B[a]P was not enhanced when the concentration was increased to 50 microM. The similarity in efficacy among the selenazolidines against B[a]P mutagenicity, contrasted with inter-compound differences in their ability to inhibit S9 CYP1A activity. The CYP1A Ki values ranged from a low of 63 microM (2-[2'-hydroxyphenyl]SCA) to a high of 1.1mM (2-cyclohexylSCA), but all were above the concentration required to inhibit mutagenicity by 50%. Thus, all the SCAs possess antimutagenic activity against both B[a]P and acridine orange, the efficacy varies little between the individual selenazolidines, and for B[a]P, the efficacy is not proportional to the inhibitory effect on the mutagen bioactivating enzyme.     

Heterologous expression and characterization of a novel halotolerant,thermostable, and alkali-stable GH6 endoglucanase from <Emphasis Type="Italic">Thermobifida halotolerans</Emphasis>

A novel endoglucanase gene was cloned from Thermobifida halotolerans YIM 90462^T, designated as thcel6A for being a member of glycoside hydrolase family 6. The gene was 1332 bp long and encoded a 443-amino-acid protein with a molecular mass of 45.9 kDa. The purified recombinant endoglucanase had optimal activity at 55 °C and pH 8.5. Thcel6A showed high hydrolytic activities at 25–55 °C and retained 58 % of initial activity after incubation at 90 °C for 1 h. It retained more than 80 % of activity after incubation for 12 h at pH values from 4 to 12. Thcel6A displayed higher hydrolytic activities in 5–15 % NaCl (w/v) than at 0 % NaCl. Activity increased 2.5-fold after incubation with 20 % (w/v) NaCl at 37 °C for 10 min. These properties suggest that this novel endoglucanase has potential for specific industrial application.     

Lack of association between orexin receptor gene polymorphisms and obstructive sleep apnea syndrome in Japanese

Sleep and Biological Rhythms - The pathogenesis of obstructive sleep apnea (OSA) is not fully understood, particularly at the genetic level. The orexins have pleiotropic effects on several aspects...     

Assessment of cardiovascular fibrosis using novel fluorescent probes

Cardiovascular fibrosis resulted from pressure overload or ischemia could alter myocardial stiffness and lead to ventricular dysfunction. Fluorescently labeled collagen-binding protein CNA 35, derived from the surface component of Staphylococcus aureus, and a novel synthetic biphenylalanine containing peptide are applied to stain fibrosis associated collagen and myocytes, respectively. Detailed pathological characteristics of cardiovascular fibrosis could be identified clearly in 2 hours. This staining pair requires only simple staining and brief washing, generating less than 10 ml of waste. The image information collected by this novel fluorescent staining pair is compatible with it collected by the traditional Masson's Trichrome and Picrosirius Red staining which are widely used to stain cardiovascular fibrosis and isolated cells.     

Reduction of 8-iso-prostaglandin F2α in the first week after Roux-en-Y gastric bypass surgery

Obesity is associated with increased markers of oxidative stress. We examined whether oxidative stress is reduced within the first week after Roux‐en‐Y gastric bypass (RYGB) surgery and could be related to changes in adipose tissue depots. The reactive oxygen species (ROS) marker 8‐iso‐prostaglandin F2α (8‐iso‐PGF2α) and activity of antioxidant glutathione peroxidases (GPX) in plasma were compared before and ～1 week after RYGB. The effects of RYGB on subcutaneous adipose tissue and interstitial fluid 8‐iso‐PGF2α levels and subcutaneous adipose tissue expression of GPX‐3 were also assessed. Levels of 8‐iso‐PGF2α in subcutaneous and visceral adipose tissue were determined. Plasma 8‐iso‐PGF2α levels decreased (122 ± 75 to 56 ± 15 pg/ml, P = 0.001) and GPX activity increased (84 ± 18 to 108 ± 25 nmol/min/ml, P = 0.003) in the first week post‐RYGB. RYGB also resulted in reductions of 8‐iso‐PGF2α in subcutaneous adipose tissue (1,742 ± 931 to 1,132 ± 420 pg/g fat, P = 0.046) and interstitial fluid (348 ± 118 to 221 ± 83 pg/ml, P = 0.046) that were comparable to plasma (26–33%, P = 0.74). Adipose GPX‐3 expression was increased (6.7 ± 4.7‐fold, P = 0.004) in the first postoperative week. The improvements in oxidative stress occurred with minimal weight loss (2.4 ± 3.4%, P = 0.031) and elevations in plasma interleukin‐6 (18.0 ± 46.8 to 28.0 ± 58.9 pg/ml, P = 0.004). Subcutaneous and visceral adipose tissues express comparable 8‐iso‐PGF2α levels (1,204 ± 470 and 1,331 ± 264 pg/g fat, respectively; P = 0.34). These data suggest that RYGB affects adipose tissue leading to the restoration of adipose redox balance within the first postoperative week and that plasma 8‐iso‐PGF2α is primarily derived from subcutaneous adipose tissue.     

Craniectomy for malignant cerebral infarction: prevalence and outcomes in US hospitals

Object

Randomized trials have demonstrated the efficacy of craniectomy for the treatment of malignant cerebral edema following ischemic stroke. We sought to determine the prevalence and outcomes related to this by using a national database.

Methods

Patient discharges with ischemic stroke as the primary diagnosis undergoing craniectomy were queried from the US Nationwide Inpatient Sample from 1999 to 2008. A subpopulation of patients was identified that underwent thrombolysis. Two primary end points were examined: in-hospital mortality and discharge to home/routine care. To facilitate interpretations, adjusted prevalence was calculated from the overall prevalence and two age-specific logistic regression models. The predictive margin was then generated using a multivariate logistic regression model to estimate the probability of in-hospital mortality after adjustment for admission type, admission source, length of stay, total hospital charges, chronic comorbidities, and medical complications.

Results

After excluding 71,996 patients with the diagnosis of intracranial hemorrhage and posterior intracranial circulation occlusion, we identified 4,248,955 adult hospitalizations with ischemic stroke as a primary diagnosis. The estimated rates of hospitalizations in craniectomy per 10,000 hospitalizations with ischemic stroke increased from 3.9 in 1999–2000 to 14.46 in 2007–2008 (p for linear trend<0.001). Patients 60+ years of age had in-hospital mortality of 44% while the 18–59 year old group was found to be 24%(p = 0.14). Outcomes were comparable if recombinant tissue plasminogen activator had been administered.

Conclusions

Craniectomy is being increasingly performed for malignant cerebral edema following large territory cerebral ischemia. We suspect that the increase in the annual incidence of DC for malignant cerebral edema is directly related to the expanding collection of evidence in randomized trials that the operation is efficacious when performed in the correct patient population. In hospital mortality is high for all patients undergoing this procedure.     

In vitro study of flavonoids, fatty acids, and steroids on proliferation of rat hepatic stellate cells

There is a wealth of evidence that hepatic stellate cells (HSCs) orchestrate most of the important events in liver fibrogenesis. After liver injury, HSCs become activated to a profibrogenic myofibroblastic phenotype and can regulate net deposition of collagens and other matrix proteins in the liver. The proliferation of HSCs is mainly stimulated by the platelet-derived growth factor (PDGF). In this study, some compounds from natural resources have been tested for their activity to inhibit PDGF-driven proliferative activity of rat HSCs. Apigenin, quercetin, genistein, daidzin, and biochanin A exhibited > 75% inhibitory activity against HSC-T6. It was found that, gamma-linolenic (gamma-Ln), eicosapentanoic (EPA) and a- linolenic (alpha-Ln) acids showed a high inhibitory effect on proliferation of rat HSCs at 50 nmol/1. Cholest-4-ene-3,6-dione and stigmastone-4-en-3,6-dione are the most active steroids with inhibitory activities > 80% and this is most likely due to the presence of the 4-en-3,6-dione moiety in both compounds. These results revealed that the compounds which effectively blocked HSC proliferation may be beneficial in liver fibrosis. Structure-activity relationships (SAR) may provide a basis for rational structure modification.     

Kinetics and mechanism of a reaction catalyzed by PST-01 protease from Pseudomonas aeruginosa PST-01

The initial rates of carboxybenzoyl-alanyl-l-leucyl-amide (Z-L-Ala-L-Leu-NH(2)) synthesis from carboxybenzoyl-L-alanine (Z-L-Ala) and L-leucineamide (L-Leu-NH(2)) and Z-L-Ala-L-Leu-NH(2) hydrolysis in a homogeneous dimethyl sulfoxide-aqueous buffer solution [1:1 (v/v)] system catalyzed by PST-01 protease from Pseudomonas aeruginosa were measured under a wide range of Z-L-Ala, L-Leu-NH(2) and Z-L-Ala-L-Leu-NH(2) concentrations. The initial rates of the synthetic reaction, in which Z-L-Ala-L-Leu-NH(2) was produced from Z-L-Ala and L-Leu-NH(2), were inhibited by the substrates. Furthermore, the initial rates of the synthetic reaction were not inhibited by the product Z-L-Ala-L-Leu-NH(2), and those of the hydrolytic reaction were inhibited by Z-L-Ala and L-Leu-NH(2). All the initial rate data of the synthetic and hydrolytic reactions were well correlated with the rate equation derived based on the proposed reaction scheme.