Functional consequences of polyamine synthesis inhibition by L-alpha-difluoromethylornithine (DFMO): cellular mechanisms for DFMO-mediated ototoxicity

L-Alpha-difluoromethylornithine (DFMO) is a chemopreventive agent for colon cancer in clinical trials. Yet, the drug produces an across-frequency elevation of the hearing threshold, suggesting that DFMO may affect a common trait along the cochlear spiral. The mechanism for the ototoxic effects of DFMO remains uncertain. The cochlear duct is exclusively endowed with endocochlear potential (EP). EP is a requisite for normal sound transduction, as it provides the electromotive force that determines the magnitude of the receptor potential of hair cells. EP is generated by the high throughput of K(+) across cells of the stria vascularis, conferred partly by the activity of Kir4.1 channels. Here, we show that the ototoxicity of DFMO may be mediated by alteration of the inward rectification of Kir4.1 channels, resulting in a marked reduction in EP. These findings are surprising given that the present model for EP generation asserts that Kir4.1 confers the outflow of K(+) in the stria vascularis. We have proposed an alternative model. These findings should also enable the rational design of new pharmaceuticals devoid of the untoward effect of DFMO.     

Movement, toxicity, and persistence of imidacloprid in seedling Tabasco pepper infested with Myzus persicae (Hemiptera: Aphididae)

Application of imidacloprid to the soil in which Tabasco pepper, Capsicum frutescens L., seedlings were growing was highly effective against the green peach aphid, Myzus persicae (Sulzer) (Hemiptera: Aphididae). In just 48 h after the soil drench, aphid numbers on treated plants declined from 292.1 to 33.0 per plant, a reduction of 89%. By 72 and 96 h after the application, the reductions were 97 and 100%, respectively. Reductions in green peach aphid numbers also indicated that imidacloprid readily moved throughout the Tabasco pepper plant. Although, initial green peach aphid reductions at 24 and 48 h after imidacloprid application to soil, were greater on the lower leaves than on the upper leaves, by 72 h toxicity was high throughout the plant. At 48 h, overall green peach aphid reduction on seedlings grown in wet soil was significantly higher than that on plants growing in the drier soil. Regardless of soil moisture or leaf location, no live green peach aphids were detected on treated seedlings after 96 h. After the initial uptake period, toxicity to green peach aphid remained high for 5 wk. Under Tabasco pepper production conditions in Central America, the greatest need for aphid management is just after transplanting. Imidacloprid soil drenches before transplanting should offer the Tabasco pepper producer an extended period of aphid-free production.     

The Effect of Chitosan as Internal or External Coating on the 5-ASA Release from Calcium Alginate Microparticles

The effect of chitosan as internal or external coating on the mesalamine (5-ASA) release from calcium alginate microparticles (CaAl) was studied, and a delayed release of 5-ASA system intended for colonic drug delivery was developed. The external chitosan coating was developed by immersion of wetted CaAl in chitosan solution and the internal coating by mixing 5-ASA with chitosan solution and drying before the preparation of CaAl. Both systems were coated with Acryl-EZE^® using combined fluid bed coating and immersion procedure. The results showed that in phosphate medium (pH 7.5), chitosan as 5-ASA coating promotes a quick erosion process accelerating drug release, but chitosan as external coating (CaAlCS) does not increase the T ₅₀ value compared with the microparticles without chitosan (CaAl). Chitosan as internal or external coating was not effective to avoid the quick 5-ASA release in acidic medium (pH 1.2). The presence of β-glucosidase enzymes increases significantly the 5-ASA release for CaAl, while no effect was observed with chitosan as internal or external coating. Fourier transform infrared spectroscopy, thermogravimetric analysis, and X-ray data revealed that 5-ASA did not form a solid solution but was dispersed in the microparticles. The Acryl-EZE^® coating of microparticles was effective because all the formulations showed a low release, less than 15%, of 5-ASA in acid medium at pH 1.2. Significant differences in the percentage of 5-ASA released between formulations were observed in phosphate buffer at pH 6.0. In phosphate buffer at pH 7.2, all the formulations released 100% of 5-ASA.     

Significant In Vivo Anti-Inflammatory Activity of Pytren4Q-Mn a Superoxide Dismutase 2 (SOD2) Mimetic Scorpiand-Like Mn (II) Complex

Background

The clinical use of purified SOD enzymes has strong limitations due to their large molecular size, high production cost and immunogenicity. These limitations could be compensated by using instead synthetic SOD mimetic compounds of low molecular weight.

Background/Methodology

We have recently reported that two SOD mimetic compounds, the Mn^II complexes of the polyamines Pytren2Q and Pytren4Q, displayed high antioxidant activity in bacteria and yeast. Since frequently molecules with antioxidant properties or free-radical scavengers also have anti-inflammatory properties we have assessed the anti-inflammatory potential of Pytren2Q and Pytren4Q Mn^II complexes, in cultured macrophages and in a murine model of inflammation, by measuring the degree of protection they could provide against the cellular injury produced by lipopolisacharide, a bacterial endotoxin.

Principal Findings

In this report we show that the Mn^II complex of Pytren4Q but not that of Pytren2Q effectively protected human cultured THP-1 macrophages and whole mice from the inflammatory effects produced by LPS. These results obtained with two molecules that are isomers highlight the importance of gathering experimental data from animal models of disease in assessing the potential of candidate molecules.

Conclusion/Significance

The effective anti-inflammatory activity of the Mn^II complex of Pytren4Q in addition to its low toxicity, water solubility and ease of production would suggest it is worth taking into consideration for future pharmacological studies.     

Brief communication: Identification of bone formation and resorption surfaces by reflected light microscopy

Developmental and evolutionary changes in craniofacial morphology are a central issue in paleoanthropology, but the underlying bone growth processes have been scarcely studied. Relevant knowledge on bone growth dynamics can be obtained from the spatial distribution of bone formation and resorption activities. Determining these patterns from the valuable samples typically used in anthropology and palaeoanthropology necessarily implies nondestructive procedures. In this work, we present a methodology based on the analysis of high‐resolution replicas by reflected light microscopy, describing how microfeatures related to bone formation and resorption activities are recognized on both recent and fossil bone surfaces. The proposed method yields highly similar images to those obtained with scanning electron microscope and has proven its utility in an analysis of a large sample of extant and extinct hominoids. Am J Phys Anthropol 143:313–320, 2010. © 2010 Wiley‐Liss, Inc.