Studies on the chiral isomers of fonofos and fonofos oxon: II. In vitro metabolism

The in vitro metabolism of the chiral isomers of fonofos and fonofos oxon in the presence of mouse liver mixed-function oxidase and serum esterase was investigated. The metabolism of ³⁵S-labeled phenyl-(S)_P-fonofos mediated by mixed-function oxidase took place stereoselectively, resulting predominantly in (R)_P-fonofos oxon. Similarly, (R)_P-fonofos was converted to (S)_P-oxon. In each case, however, a significant amount of racemization occurred. Other products were diphenyl disulfide and diphenyl disulfide oxide. In addition to stereospecificity, the oxidative metabolism of (R)_P-fonofos proceeded at a rate faster than that of (S)_P-fonofos. Stereoselective rate differences also were observed in mouse or rat serum-catalzyed degradation of the fonofos oxon enantiomers, the (S)_P isomer being degraded about twofold faster than its enantiomer. The differences in toxicities of the isomers of fonofos and fonofos oxon were consistent with the in vitro metabolism data.     

Evaluation of host and bacterial gene modulation during Lawsonia intracellularis infection in immunocompetent C57BL/6 mouse model

BackgroundProliferative enteritis caused by Lawsonia intracellularis undermines the economic stability of the swine industry worldwide. The development of cost-effective animal models to study the pathophysiology of the disease will help develop strategies to counter this bacterium.ObjectivesThis study focused on establishing a model of gastrointestinal (GI) infection of L. intracellularis in C57BL/6 mice to evaluate the disease progression and lesions of proliferative enteropathy (PE) in murine GI tissue.MethodsWe assessed the murine mucosal and cell-mediated immune responses generated in response to inoculation with L. intracellularis.ResultsThe mice developed characteristic lesions of the disease and shed L. intracellularis in the feces following oral inoculation with 5 × l0⁷ bacteria. An increase in L. intracellularis 16s rRNA and groEL copies in the intestine of infected mice indicated intestinal dissemination of the bacteria. The C57BL/6 mice appeared capable of modulating humoral and cell-mediated immune responses to L. intracellularis infection. Notably, the expression of genes for the vitamin B12 receptor and for secreted and membrane-bound mucins were downregulated in L. intracellularis -infected mice. Furthermore, L. intracellularis colonization of the mouse intestine was confirmed by the immunohistochemistry and western blot analyses.ConclusionsThis is the first study demonstrating the contributions of bacterial chaperonin and host nutrient genes to PE using an immunocompetent mouse model. This mouse infection model may serve as a platform from which to study L. intracellularis infection and develop potential vaccination and therapeutic strategies to treat PE.     

An Octopus-Derived Peptide with Antidiuretic Activity in Rats

Discovering new drug candidates with high efficacy and few side effects is a major challenge in new drug development. The two evolutionarily related peptides oxytocin (OXT) and arginine vasopressin (AVP) are known to be associated with a variety of physiological and psychological processes via the association of OXT with three types of AVP receptors. Over decades, many synthetic analogs of these peptides have been designed and tested for therapeutic applications; however, only a few studies of their natural analogs have been performed. In this study, we investigated the bioactivity and usefulness of two natural OXT/AVP analogs that originate from the marine invertebrate Octopus vulgaris, named octopressin (OTP) and cephalotocin (CPT). By measuring the intracellular Ca²⁺ or cyclic AMP increase in each OXT/AVP receptor subtype–overexpressing cell, we found that CPT, but not OTP, acts as a selective agonist of human AVP type 1b and 2 receptors. This behavior is reminiscent of desmopressin, the most widely prescribed antidiuretic drug in the world. Similar to the case for desmopressin, a single intravenous tail injection of CPT into Sprague-Dawley rats reduced urine output and increased urinary osmolality. In conclusion, we suggest that CPT has a significant antidiuretic effect and that CPT might be beneficial for treating urological conditions such as nocturia, enuresis, and diabetes insipidus.     

The response of cylindrocladium conidia to soil fungistasis

Direct observation of washed conidia of Cylindrocladium scoparium on non-sterile soils, air dried and rewetted immediately before deposition of conidia, indicated that peak germination (33–58%) occurred after 24 h incubation at 26°C. Peak germination on continually moist soils was lower (18–26%) than on rewetted soils. Lysis of germ tubes and germinating conidia on continually moist soils at 26°C was evident with 48 h. Conidia did not germinate on continually moist soils at 6°C and lysis did not become apparent until 168 h. Conidia germinated at a high level (93–99%) in axenic culture in the absence of exogenous C and N sources. The inhibition of conidial germination on soils may be attributed, in part, to the presence of soil volatiles. Germination of conidia placed on washed agar disks and exposed to volatiles from four soils ranged from 51 to 86% of the no-soil controls. Addition of carbon (13 ng C per conidium as glucose) and nitrogen (65 pg N ng^?1 C as NH₄C1) nullified the inhibitory effect of the soil volatiles. Germinability assayed on a selective medium at 26°C of conidia in artificially infested soils (approximately 10⁴ conidia g^?1 soil) decreased progressively during incubation at 26°C from 1 week to 4 months. No germinable conidia were recovered from artificially infested soils after 2 months incubation at 6°C. Conidia of C. floridanum and C. crotalariae responded similarly to C. scoparium in many assays.