Design and synthesis of novel imidazoline derivatives with potent antihyperglycemic activity in a rat model of type 2 diabetes

Imidazoline derivatives have been reported to show antihyperglycemic activity in vivo. In the present study, we first showed that there was no correlation between the in vivo antidiabetic activity and the in vitro affinities for the I1/I2 binding sites for several substituted aryl imidazolines. Among these compounds, 2-(alpha-cyclohexyl-benzyl)-4,5-dihydro-1H-imidazole 2 exhibited potent antihyperglycemic properties. It was then chosen as lead compound. Thirty-six new derivatives were synthesized by replacing the cyclohexyl/benzyl group by various cyclic systems or the imidazoline ring by isosteric heterocycles. These compounds were evaluated in vivo for their antihyperglycemic activity using an oral glucose tolerance test (OGTT) in a rat model of type-2 diabetes obtained by giving a single intravenous (iv) injection of a low dose of streptozotocin to rats (STZ rats) and in normal rats. Nine compounds with an imidazoline moiety, possibly substituted by a methyl group, had a potent effect on the glucose tolerance in normal or STZ-diabetic rats, after an oral (po) administration of the test compound at a dose of 30 or 10 mg kg(-1), without any hypoglycemia. Replacement of the imidazoline ring by isosteric heterocycles resulted in a total loss of activity.     

Ecological risk assessment in a tropical wetland contaminated with gasoline: Tier 1

To assess natural attenuation and the efficiency of remediation actions after more than two years a large accident with gasoline spill contaminated a wetland in a tropical region, an Ecological Risk Assessment based on the Dutch Triad was applied. In total, eight surface water-sampling points were distributed randomly in the affected area and on reference area upstream the contaminated site, with similar ecological characteristics. Risks based on chemical, ecotoxicological, and ecological lines of evidence (LoE) were calculated to integrate the environmental risk indexes. The chemical risk was derived from toxic pressure coefficients based on the total BTEX and naphthalene concentrations. Ecotoxicological LoE based on acute toxicity with Daphnia similis and Aliivibrio fischeri bioassays and chronic toxicity with Desmodesmus subspicatus bioassay contributed to raise uncertainty due to low sensitivity of acute assays. Genotoxicity and endocrine disruption biomarkers of Oreochromis niloticus were used to calculate the Biomarker Stress Index (BSI) assumed as Ecological Risk Index. The integration of the Chemical Risk Index with BSI to estimate the Biological Vulnerability Index allowed a meaningful analysis of the threats to the aquatic ecosystem, thereby supporting managers and decision-makers.     

Hourly activity of Lutzomyia neivai in the endemic zone of cutaneous leishmaniasis in Tucumán, Argentina: preliminary results

In the present work, the hourly activity of Lutzomyia neivai was studied in the southern part of the province of Tucumán, Argentina, in an area of transmission of cutaneous leishmaniasis during two months of higher activity. In addition, the variables that influenced the abundance of Lu. neivai were evaluated. A total of 1,146 individuals belonging to Lu. neivai (97%) and Lutzomyia migonei (3%) were captured. The hourly activity of Lu. neivai was mainly nocturnal, with a bimodal pattern in both months. In January, the variable that most influenced the abundance of Lu. neivai was the temperature, whereas in April, that variable was humidity. These results may contribute to the design of anti-vectorial control measures at a micro-focal scale.     

Nonhematopoietic cells are key players in innate control of bacterial airway infection

Airborne pathogens encounter several hurdles during host invasion, including alveolar macrophages (AMs) and airway epithelial cells (AECs) and their products. Although growing evidence indicates pathogen-sensing capacities of epithelial cells, the relative contribution of hematopoietic versus nonhematopoietic cells in the induction of an inflammatory response and their possible interplay is still poorly defined in vivo in the context of infections with pathogenic microorganisms. In this study, we show that nonhematopoietic cells, including AECs, are critical players in the inflammatory process induced upon airway infection with Legionella pneumophila, and that they are essential for control of bacterial infections. Lung parenchymal cells, including AECs, are not infected themselves by L. pneumophila in vivo but rather act as sensors and amplifiers of inflammatory cues delivered by L. pneumophila-infected AM. We identified AM-derived IL-1β as the critical mediator to induce chemokine production in nonhematopoietic cells in the lung, resulting in swift and robust recruitment of infection-controlling neutrophils into the airways. These data add a new level of complexity to the coordination of the innate immune response to L. pneumophila and illustrate how the cross talk between leukocytes and nonhematopoietic cells contributes to efficient host protection.     

Involvement of L-type calcium channel and SERCA2a in myocardial dysfunction induced by obesity

Obesity has been shown to impair myocardial performance. Nevertheless, the mechanisms underlying the participation of calcium (Ca(2+) ) handling on cardiac dysfunction in obesity models remain unknown. L-type Ca(2+) channels and sarcoplasmic reticulum (SR) Ca(2+) -ATPase (SERCA2a), may contribute to the cardiac dysfunction induced by obesity. The purpose of this study was to investigate whether myocardial dysfunction in obese rats is related to decreased activity and/or expression of L-type Ca(2+) channels and SERCA2a. Male 30-day-old Wistar rats were fed standard (C) and alternately four palatable high-fat diets (Ob) for 15 weeks. Obesity was determined by adiposity index and comorbidities were evaluated. Myocardial function was evaluated in isolated left ventricle papillary muscles under basal conditions and after inotropic and lusitropic maneuvers. L-type Ca(2+) channels and SERCA2a activity were determined using specific blockers, while changes in the amount of channels were evaluated by Western blot analysis. Phospholamban (PLB) protein expression and the SERCA2a/PLB ratio were also determined. Compared with C rats, the Ob rats had increased body fat, adiposity index and several comorbidities. The Ob muscles developed similar baseline data, but myocardial responsiveness to post-rest contraction stimulus and increased extracellular Ca(2+) was compromised. The diltiazem promoted higher inhibition on developed tension in obese rats. In addition, there were no changes in the L-type Ca(2+) channel protein content and SERCA2a behavior (activity and expression). In conclusion, the myocardial dysfunction caused by obesity is related to L-type Ca(2+) channel activity impairment without significant changes in SERCA2a expression and function as well as L-type Ca(2+) protein levels.     

Occurrence and development of Eucryptorrhynchus brandti and E. chinensis (Coleoptera: Curculionidae) on Ailanthus altissima trees subjected to different levels of mechanical damage

Eucryptorrhynchus brandti (Harold) and E. chinensis (Oliver) are herbivores of Ailanthus altissima (Mill.) Swingle (tree of heaven) in China. Eucryptorrhynchus brandti has been recommended as a potential biological control agent of A. altissima in North America. In China, the majority of adults of both species were found on tree trunks 0–5 m above the ground, from May to September. In October and November, most adults were found at the base of A. altissima trees. Trees were subjected to different levels of mechanical injury: very low mechanical injury, one to two 0.015 m² bark sections were removed; low, two to four bark sections were removed; moderate, 8 to 22 bark sections removed; high, tree was girdled; and extreme, tree was felled and the remaining stump was sampled. Very low and low mechanical injury trees had very few adult emergence holes with few larvae developing beyond the first or second instar after 29 months. The health of these trees remained good. An increase in adult emergence holes occurred in moderately injured trees that appeared as healthy as very low to low mechanically injured trees. This may indicate that only a small increase in tree stress can increase the adult emergence rate and thus hasten a decline in tree health. Moderate, high and extreme mechanically injured trees had significantly more emergence holes/m than very low and low injured trees and late larval stages were present. The development of Eucryptorrhynchus species was more successful the greater the degree of mechanical injury. Based on this study both Eucryptorrhynchus species appear to be secondary pests of A. altissima in China.     

Survey of Verticillium nonalfalfae (Phyllachorales) on tree-of-heaven in the southeastern USA

Ailanthus altissima (Mill.) Swingle commonly known as tree-of-heaven is an invasive tree species that has spread through much of the USA. Significant mortality of A. altissima by a highly host-specific strain of the fungus, Verticillium nonalfalfae Inderb. (formerly Verticillium albo-atrum Reinke and Bethold), has been recently documented in Pennsylvania. To detect the regional distribution of this biological control agent in the Southeast, a windshield survey was conducted in Virginia, North Carolina and South Carolina to locate V. nonalfalfae-infected A. altissima stands. The survey covered 26,500 km of interstate highways and primary and secondary roads. There were 90 potential sites located throughout the three states. Of those, six were found to be infested with the fungus, all in the mountain regions of Virginia. Inoculation tests suggest no difference in virulence among the six V. nonalfalfae isolates on A. altissima, which resulted in 100% mortality in 9–11 weeks post-inoculation. Tree ratings revealed differences in health among sites, but all sites had an increase in disease incidence from 2011 to 2012 (mean = 4.7 ± 3.8%), suggesting this fungus is dispersing. This survey provides evidence that biological control using this fungus may be possible in Virginia.     

Jasmonate‐dependent modifications of the pectin matrix during potato development function as a defense mechanism targeted by Dickeya dadantii virulence factors

The plant cell wall constitutes an essential protection barrier against pathogen attack. In addition, cell‐wall disruption leads to accumulation of jasmonates (JAs), which are key signaling molecules for activation of plant inducible defense responses. However, whether JAs in return modulate the cell‐wall composition to reinforce this defensive barrier remains unknown. The enzyme 13–allene oxide synthase (13–AOS) catalyzes the first committed step towards biosynthesis of JAs. In potato (Solanum tuberosum), there are two putative St13–AOS genes, which we show here to be differentially induced upon wounding. We also determine that both genes complement an Arabidopsis aos null mutant, indicating that they encode functional 13–AOS enzymes. Indeed, transgenic potato plants lacking both St13–AOS genes (CoAOS1/2 lines) exhibited a significant reduction of JAs, a concomitant decrease in wound‐responsive gene activation, and an increased severity of soft rot disease symptoms caused by Dickeya dadantii. Intriguingly, a hypovirulent D. dadantii pel strain lacking the five major pectate lyases, which causes limited tissue maceration on wild‐type plants, regained infectivity in CoAOS1/2 plants. In line with this, we found differences in pectin methyl esterase activity and cell‐wall pectin composition between wild‐type and CoAOS1/2 plants. Importantly, wild‐type plants had pectins with a lower degree of methyl esterification, which are the substrates of the pectate lyases mutated in the pel strain. These results suggest that, during development of potato plants, JAs mediate modification of the pectin matrix to form a defensive barrier that is counteracted by pectinolytic virulence factors from D. dadantii.