Efficacy and dosing of antidotes applied to Daphnia intoxicated by nerve agent tabun

A new assay with Daphnia, which can be used as a time, cost, and human effort-saving tool in the development of effective antidotes against organophosphate intoxications, is presented. Five concentrations of atropine (antimuscarinic anticholinergics) as well as a reactivator (trimedoxime) were tested to define the optimal dosage. Various reactivators (trimedoxime, obidoxime) were used to examine difference in effectivity of treatments. The most effective dose of trimedoxime corresponded to the 75% of its EC(50)(24) value, i.e. 77.85mgl(-1). The most effective dose of atropine corresponded to the 25% of its EC(50)(24) value, i.e. 104.70mgl(-1). The most effective treatment was a combined atropine-obidoxime treatment, followed by the combined atropine-trimedoxime treatment, the atropine only and the obidoxime only treatments. The efficacy of the trimedoxime only treatment was doubtful. The surprisingly high efficacy of obidoxime in the obidoxime only treatment indicates that some oximes might act in daphnids not just as reactivators but also by some other mechanisms.     

JNK inhibitor SP600125 is a partial agonist of human aryl hydrocarbon receptor and induces CYP1A1 and CYP1A2 genes in primary human hepatocytes

SP600125, a specific inhibitor of c-Jun-N-Terminal kinase (JNK), was reported as a ligand and antagonist of aryl hydrocarbon receptor (AhR) [Joiakim A, Mathieu PA, Palermo C, Gasiewicz TA, Reiners Jr JJ. The Jun N terminal kinase inhibitor SP600125 is a ligand and antagonist of the aryl hydrocarbon receptor. Drug Metab Dispos 2003;31(11):1279-82]. Here we show that SP600125 is not an antagonist but a partial agonist of human AhR. SP600125 significantly induced CYP1A1 and CYP1A2 mRNAs in primary human hepatocytes and CYP1A1 mRNA in human hepatoma cells HepG2. This effect was abolished by resveratrol, an antagonist of AhR. Consistent with the recent report, SP600125 dose-dependently inhibited CYP1A1 and CYP1A2 genes induction by a prototype AhR ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in human hepatocytes. Moreover, SP600125 displayed typical behavior of a partial agonist in HepG2 cells transiently transfected with a reporter plasmid containing two inverted repeats of the dioxin responsive element or with a plasmid containing 5'-flanking region of human CYP1A1 gene. SP600125 transactivated the reporter plasmids with EC(50) of 0.005 and 1.89 microM, respectively. On the other hand, TCDD-dependent transactivation of the reporter plasmids was inhibited by SP600125 with IC(50) values of 1.54 and 2.63 microM, respectively. We also tested, whether the effects of SP600125 are due to metabolism. Using liquid chromatography/mass spectrometry approach, we observed formation of two minor monohydroxylated metabolites of SP600125 in human hepatocytes, human liver microsomes but not in HepG2 cells. These data imply that biotransformation is not responsible for the effects of SP600125 on AhR signaling. In conclusion, we demonstrate that SP600125 is a partial agonist of human AhR, which induces CYP1A genes.     

Sanguinarine and chelerythrine: assessment of safety on pigs in ninety days feeding experiment.

Sanguinaria canadesis, Chelidonium majus and Macleya cordata have been used for centuries as alternative medicines. Currently the extracts from these medicinal plants are components of veterinary and human phytopreparations, and of oral-hygiene agents. Sanguinarine and chelerythrine (SA/CHE) are biologically active components of these extracts. They display distinct antibacterial and anti-inflammatory properties, but, on the other hand, they have been reported as having adverse effects - genotoxicity and hepatotoxicity. This paper is aimed at evaluation of the effects of daily administration of the extract from Macleya cordata (2 mg and 100 mg in 1 kg feed, sanguinarine:chelerythrine 3:1) in the diet on the health status of swine. After 90-day administration, alkaloids were retained to a different extent in tissues. The highest SA/CHE retention was detected in the gingiva (0.55 microg/g) and liver (0.15 microg/g), no SA/CHE were detected in muscles. Plasma SA levels attained 0.11 microg/ml. Treated animals did not display any results of hematological, biochemical or histological assay different from controls. A (32)P-postlabeling assay proved that no DNA-adducts with SA/CHE were detected in pig livers. We did not observe any symptom linked to epidemic dropsy syndrome often attributed to sanguinarine. In conclusion, an average daily oral dose of alkaloids up to 5 mg per 1 kg animal body weight proved to be safe.     

Coat as a Dagger: The Use of Capsid Proteins to Perforate Membranes during Non-Enveloped DNA Viruses Trafficking

To get access to the replication site, small non-enveloped DNA viruses have to cross the cell membrane using a limited number of capsid proteins, which also protect the viral genome in the extracellular environment. Most of DNA viruses have to reach the nucleus to replicate. The capsid proteins involved in transmembrane penetration are exposed or released during endosomal trafficking of the virus. Subsequently, the conserved domains of capsid proteins interact with cellular membranes and ensure their efficient permeabilization. This review summarizes our current knowledge concerning the role of capsid proteins of small non-enveloped DNA viruses in intracellular membrane perturbation in the early stages of infection.     

Cortico-spinal excitability and hand motor recovery in stroke: a longitudinal study

Objective

To describe the relationship between changes of cortico-spinal excitability and motor recovery of the affected hand after stroke.

Methods

Eighteen hemiparetic stroke patients with a severe-to-mild upper limb motor impairment were randomized. Cortico-spinal excitability measures (resting motor thresholds and motor evoked potentials) obtained from a distal (abductor pollicis brevis) and proximal (biceps brachii) upper limb muscle were assessed for both hemispheres. Motor function of the affected hand was tested by the Wolf Motor Function and Action Research Arm tests. The evaluations were performed at baseline and weekly over 7 weeks of in-patient neurological rehabilitation.

Results

Severe hand dysfunction was associated with a strong suppression of ipsilesional cortico-spinal excitability and a shift of excitability towards the contralesional hemisphere. Mild hand impairment was associated with a shift of cortico-spinal excitability towards the ipsilesional hemisphere. Favorable motor recovery correlated with an increase of ipsilesional cortico-spinal excitability.