Impact of cholesterol on ABC and SLC transporters expression and function and its role in disposition variability to lipid-lowering drugs

This report focuses on the effects of cholesterol on the expression and function of the ATP-binding cassette (ABCB1, ABCG2 and ABCC2) and solute-linked carrier (SLCO1B1 and SLCO2B1) drug transporters with a particular focus on the potential impact of cholesterol on lipid-lowering drug disposition. Statins are the most active agents in the treatment of hypercholesterolemia. However, considerable interindividual variation exists in the response to statin therapy. Therefore, it would be huge progress if factors were identified that reliably differentiate between responders and nonresponders. Many studies have suggested that plasma lipid concentrations can affect drug disposition of compounds, such as ciclosporin and amphotericin B. Both compounds are able to affect the expression and function of ABC transporters. Although still speculative, these effects might be owing to the regulation of drug transporters by plasma cholesterol levels. Studies with normo- and hyper-cholesterolemic individuals, before and after atorvastatin treatment, have demonstrated that plasma cholesterol levels are correlated with drug transporter expression, as well as being related to atorvastatin`s cholesterol-lowering effect. The mechanism influencing the correlation between cholesterol levels and the expression and function of drug transporters remains unclear. Some studies provide strong evidence that nuclear receptors, such as the pregnane X receptor and the constitutive androstane receptor, mediate this effect. In the near future, pharmacogenomic studies with individuals in a pathological state should be performed in order to identify whether high plasma cholesterol levels might be a factor contributing to interindividual oral drug bioavailability.

Mitochondrial function in the yeast form of the pathogenic fungus Paracoccidioides brasiliensis

Differences between the respiratory chain of the fungus Paracoccidioides brasiliensis and its mammalian host are reported. Respiration, membrane potential, and oxidative phosphorylation in mitochondria from P. brasiliensis spheroplasts were evaluated in situ, and the presence of a complete (Complex I-V) functional respiratory chain was demonstrated. In succinate-energized mitochondria, ADP induced a transition from resting to phosphorylating respiration. The presence of an alternative NADH-ubiquinone oxidoreductase was indicated by: (i) the ability to oxidize exogenous NADH and (ii) the lack of sensitivity to rotenone and presence of sensitivity to flavone. Malate/NAD(+)-supported respiration suggested the presence of either a mitochondrial pyridine transporter or a glyoxylate pathway contributing to NADH and/or succinate production. Partial sensitivity of NADH/succinate-supported respiration to antimycin A and cyanide, as well as sensitivity to benzohydroxamic acids, suggested the presence of an alternative oxidase in the yeast form of the fungus. An increase in activity and gene expression of the alternative NADH dehydrogenase throughout the yeast`s exponential growth phase was observed. This increase was coupled with a decrease in Complex I activity and gene expression of its subunit 6. These results support the existence of alternative respiratory chain pathways in addition to Complex I, as well as the utilization of NADH-linked substrates by P. brasiliensis. These specific components of the respiratory chain could be useful for further research and development of pharmacological agents against the fungus.

Chronic hyperhomocysteinemia impairs vascular function in ovariectomized rat carotid arteries

Homocysteine is an independent risk factor for coronary heart disease, as well as for cerebrovascular and peripheral vascular diseases. The purpose of this study was to investigate the effects of hyperhomocysteinemia (HHcy) on vascular reactivity within carotid artery segments isolated from ovariectomized female rats. Treatment with dl-Hcy thiolactone (1 g/kg body weight per day) reduced the phenylephrine-induced contraction of denuded rings. However, the treatment did not alter KCl-induced contractions, or relaxations induced by sodium nitroprusside or acetylcholine. We report elevated expressions of iNOS, eNOS, and nitrotyrosine in homocysteine-treated rat artery sections. Moreover, the inhibition of NOS by l-NAME, 1,400 W, or l-NNA restored phenylephrine-induced vasoconstriction in carotid artery segments from Hcy-treated rats. In conclusion, our findings show that severe HHCy can promote an acute decrease in the endothelium-independent contractile responses of carotid arteries to adrenergic agonists. This effect was restored by nitric oxide synthase inhibitors, which further supports the involvement of nitric oxide in HHcy-derived vascular dysfunction.

Inflorescence and floral development of Dahlstedtia species (Leguminosae: Papilionoideae: Millettieae)

Inflorescence and floral development of two tropical legume trees, Dahlstedtia pinnata and Dahlstedlia pentaphylla, occurring in the Atlantic Forest of south-eastern and southern Brazil, were investigated and compared with other papilionoids. Few studies have been made of floral development in tribe Millettieae, and this paper is intended to fill that gap in our knowledge. Dahlstedtia species have an unusual inflorescence type among legumes, the pseudoraceme, which comprises axillary units of three or more flowers, each with a subtending bract. Each flower exhibits a pair of opposite bractcoles. The order of flower initiation is acropetal; inception of the floral organs is as follows: sepals (5), petals (5), carpel (1) plus outer stamens (5) and finally inner stamens (5). Organ initiation in sepal, petal and inner stamen whorls is unidirectional; the carpel cleft is adaxial. The vexillum originates from a tubular-shaped primordium in mid-development and is larger than other petals at maturity, covering the keels. The filament tube develops later after initiation of inner-stamen primordia. Floral development in Dahlstedtia is almost always similar to other papilionoids, especially species of Phaseoleae and Sophoreae. But one important difference is the precocious ovule initiation (open carpel with ovules) in Dahlstedtia, the third citation of this phenomenon for papilionoids. No suppression, organ loss or anomalies occur in the order of primordia initiation or structure. Infra-generic differences in the first stages of ontogeny are rare; however, different species of Dahlstedtia are distinguished by the differing distribution pattern of secretory cavities in the flower. (C) 2009 Elsevier GmbH. All rights reserved.

Paste Residence Time in a Spouted Bed Dryer. IV: Effect of the Inert Particle Size Distribution

The residence time distribution and mean residence time of a 10% sodium bicarbonate solution that is dried in a conventional spouted bed with inert bodies were measured with the stimulus-response method. Methylene blue was used as a chemical tracer, and the effects of the paste feed mode, size distribution of the inert bodies, and mean particle size on the residence times and dried powder properties were investigated. The results showed that the residence time distributions could be best reproduced with the perfect mixing cell model or N = 1 for the continuous stirred tank reactor in a series model. The mean residence times ranged from 6.04 to 12.90 min and were significantly affected by the factors studied. Analysis of variance on the experimental data showed that mean residence times were affected by the mean diameter of the inert bodies at a significance level of 1% and by the size distribution at a level of 5%. Moreover, altering the paste feed from dripping to pneumatic atomization affected mean residence time at a 5% significance level. The dried powder characteristics proved to be adequate for further industrial manipulation, as demonstrated by the low moisture content, narrow range of particle size, and good flow properties. The results of this research are significant in the study of the drying of heat-sensitive materials because it shows that by simultaneously changing the size distribution and average size of the inert bodies, the mean residence times of a paste can be reduced by half, thus decreasing losses due to degradation.