Disappearance rates of radiation-induced chromosome aberrations from swine leukocytes

Whole-blood leukocyte cultures were evaluated at intervals up to 20 weeks following the exposure of mature pigs to 150 or 200 R whole-body doses of γ-radiation. Lymphocyte number was depressed to approximately 35% of preirradiation values by 48 h postexposure; chromosome aberration levels also quite drastically during this period. A rapid decrease in aberrations per cell indicated selective removal of cells containing chromosome anomalues during the early postirradiation period. Elevated levels of both one-track and two-track aberrations persisted at 20 weeks although the former had been at preirradiation levels at 12 and 16 weeks.     

Regulation of conceptus adhesion by endometrial CXC chemokines during the implantation period in sheep

To gain a better understanding of biochemical mechanisms of conceptus adhesion to the maternal endometrium in ruminant ungulates, the present study was performed to clarify roles of chemokines and extracellular matrix (ECM) components in the regulation of ovine blastocyst attachment to the endometrium. In addition to the chemokine, interferon-gamma inducible protein 10 kDa (IP-10, CXCL10), the chemokine receptor, CXCR3, also recognizes two other chemokines; monokine induced by IFN-gamma (MIG, CXCL9) and IFN-inducible T cell alpha chemoattractant (I-TAC, CXCL11). Similar to CXCL10, CXCL9, and CXCL11 were expressed in the uterus during the peri-implantation period, and CXCL9 mRNA expression was stimulated in endometrial explants from day 14 cyclic ewes by the addition of IFN-tau or IFN-gamma. Without ECM components, conceptus cell adhesion was low on day 14 of gestation and exhibited a 2.5-fold increase on day 17; adhesiveness on day 20 was 1/10 of that on day 14. Among various ECM components examined, trophoblast adhesion was greatest when fibronectin was used. Although day 14 conceptuses did not show much adhesive activity to fibronectin, day 17 trophoblast, and day 20 chorionic membrane exhibited 2.3-fold and 50-fold increase, respectively, which was enhanced by treatment with CXCL9 or CXCL10. These results indicate that through endometrial fibronectin and chemokines, ovine conceptus cells gain the ability to attach to the endometrium during pre-implantation period; however, elucidation of molecular mechanisms by which the conceptus acquires the adhesive ability during this time period awaits further investigation.     

Structure-activity relationship study of 9-aminoacridine compounds in scrapie-infected neuroblastoma cells

A focused library of variously substituted 9-aminoacridine compounds was screened for bioactivity against accumulation of the infectious prion protein isoform, denoted PrP(Sc), in a cell model of prion replication. The efficacy of compounds against PrP(Sc) accumulation was influenced by both substituents of the distal tertiary amine and acridine heterocycle, while cellular cytotoxicity was encoded in the acridine heterocycle substituents.     

Duration and intensity of NF-kappaB activity determine the severity of endotoxin-induced acute lung injury

Activation of innate immunity in the lungs can lead to a self-limited inflammatory response or progress to severe lung injury. We investigated whether specific parameters of NF-kappaB pathway activation determine the outcome of acute lung inflammation using a novel line of transgenic reporter mice. Following a single i.p. injection of Escherichia coli LPS, transient NF-kappaB activation was identified in a variety of lung cell types, and neutrophilic inflammation resolved without substantial tissue injury. However, administration of LPS over 24 h by osmotic pump (LPS pump) implanted into the peritoneum resulted in sustained, widespread NF-kappaB activation and neutrophilic inflammation that culminated in lung injury at 48 h. To determine whether intervention in the NF-kappaB pathway could prevent progression to lung injury in the LPS pump model, we administered a specific IkappaB kinase inhibitor (BMS-345541) to down-regulate NF-kappaB activation following the onset of inflammation. Treatment with BMS-345541 beginning at 20 h after osmotic pump implantation reduced lung NF-kappaB activation, concentration of KC and MIP-2 in lung lavage, neutrophil influx, and lung edema measured at 48 h. Therefore, sustained NF-kappaB activation correlates with severity of lung injury, and interdiction in the NF-kappaB pathway is beneficial even after the onset of lung inflammation.     

A comparison of the effects of prenatal exposure of CD‐1 mice to three imidazolium‐based ionic liquids

BACKGROUND: Ionic liquids (ILs; salts with melting points below 100°C) exhibit wide liquid ranges, non‐flammability, and thermal stability among other properties. These unique salts are best known as “green” alternatives to traditional volatile organic solvents, which are utilized in both academia and industry. Our current study compares the developmental toxicity potential of three representative ionic liquids, with various chain lengths: 1‐ethyl‐3‐methylimidazolium chloride ([C₂mim]Cl), 1‐butyl‐3‐methylimidazolium chloride ([C₄mim]Cl), and 1‐decyl‐3methylimidazolium chloride ([C₁₀mim]Cl). METHODS: From gestation days (GD) 6‐16, mated CD‐1 mice were orally dosed with one of the following: 1,000, 2,000, or 3,000 mg/kg/day [C₂mim]Cl; 113, 169, or 225 mg/kg/day [C₄mim]Cl; 50, 75, or 100 mg/kg/day [C₁₀mim]Cl; or the vehicle only. Dams were sacrificed on GD 17, and their litters were examined for adverse effects. RESULTS: Fetal weight was significantly decreased in the two highest dosage groups exposed to [C₄mim]Cl and [C₁₀mim]Cl in comparison with their controls, but the [C₂mim]Cl treated groups were not affected. An apparent teratogenic effect was associated with both [C₄mim]Cl and [C₁₀mim]Cl, as the offspring exhibited certain uncommon morphological defects. However, the incidences of malformations were low and no correlation between incidence and dosage could be made. No morphological defects were observed in any of the [C₂mim]Cl‐treated groups, despite maternal morbidity at the highest dosage level. CONCLUSIONS: This study indicates that [C₄mim]Cl and [C₁₀mim]Cl may have adverse effects on development at high maternal exposures and strongly supports the supposition that the toxicity of imidazolium‐based ILs is influenced by alkyl chain length. Birth Defects Res (Part B) 89:233–238, 2010. © 2010 Wiley‐Liss, Inc.     

1,4-Benzodiazepine peripheral cholecystokinin (CCK-A) receptor agonists

A series of 1,4-benzodiazepines, N-1-substituted with an N-isopropyl-N-phenylacetamide moiety, was synthesized and screened for CCK-A agonist activity. In vitro agonist activity on isolated guinea pig gallbladder along with in vivo induction of satiety following intraperitoneal administration in a rat feeding assay was demonstrated.