in silico modeling, using Psipred and ExPASy servers was employed to determine the structural elements of Bcr-Abl oncoprotein (p210BCR-ABL) isoforms, b2a2 and b3a2, expressed in Chronic Myelogenous Leukemia (CML). Both these proteins are tyrosine kinases having masses of 210-kDa and differing only by 25 amino acids coded by the b3 exonand an amino acidsubstitution (Glu903Asp). The secondary structure elements of the two proteins show differences in five α-helices and nine β-strands which relates to differences in the SH3, SH2, SH1 and DNA-binding domains. These differences can result in different roles played by the two isoforms in mediating signal transduction during the course of CML.

The structure of human Methylenetetrahydrofolate Reductase (MTHFR) is not known either by NMR or by X-ray methods. Phosphorylation seems to play an important role in the functioning of this flavoprotein. MTHFR catalyzes an irreversible reaction in homocysteine metabolism. Phosphorylation decreases the activity of MTHFR by enhancing the sensitivity of the enzyme to SAdenosylmethione. Two common polymorphisms in MTHFR, Ala222Val and Glu429Ala, can result in a number of vascular diseases. Effects of the Glu429Ala polymorphism on the structure of human MTHFR remain undetermined due to limited structural information. Hence, structural models of the MTHFR mutants were constructed using I-TASSER and assessed by PROCHECK, DFIRE and Verify3D tools. A mechanism is further suggested for the decreased activity of the Ala222Val and Glu429Ala mutants due to a decrease in number of serine phosphorylation sites using information gleaned from the molecular models. This provides insights for the understanding of structure-function relationship for MTHFR.

Because sulfonylureas directly activate the exocytotic machinery, we were interested in the extent to which these compounds penetrate the ␤-cell plasma membrane and the underlying molecular mechanism(s). We now provide evidence that sulfonylureas cross phospholipid bilayer membranes rapidly and effectively by a free-diffusion mechanism. Two sulfonylurea compounds investigated by 1 H nuclear magnetic resonance spectroscopy, glibenclamide and tolbutamide, were found to incorporate into phospholipid bilayers, with the ionizable sulfonamide exposed to the aqueous interface and its apparent dissociation constant (pK a ) increased to ϳ7.0. Diffusion of weak amphiphilic acids across membranes is associated with a measurable change in pH. Thus, by using a fluorescencebased pH assay, we could investigate the diffusion of sulfonylurea compounds across phospholipid bilayer membranes. A fluorescent pH indicator (pyranin or [2,7-bis (2-carboxyethyl)-5(6)-carboxyfluorescein] [BCECF]) was trapped in egg phosphatidylcholine vesicles. Addition of glibenclamide decreased internal pH (pH in ), and addition of albumin reversed this drop by 50%. With the same amount of tolbutamide, the decrease in pH in was much smaller, primarily because of the lower partitioning of tolbutamide into phospholipid bilayers. Using similar protocols, we also demonstrated diffusion by the same mechanism across the ␤-cell plasma membrane. Thus, we now provide a molecular mechanism by which sulfonylureas can penetrate the plasma membrane and reach intracellular sites regulating exocytosis. Diabetes 52:2526 -2531, 2003 S ulfonylureas are drugs that stimulate secretion of insulin from the pancreatic ␤-cells (1,2) and are therefore used extensively in the treatment of type 2 diabetes. It is well established that sulfonylureas stimulate insulin release by interacting with the high-affinity 140-kDa SUR1 protein of the ATP-regulated K ϩ channel at the cytoplasmic leaflet of the plasma membrane. This interaction closes the channel, causing membrane depolarization, the opening of voltage-gated L-type Ca 2ϩ channels, an increase in cytoplasmic-free Ca 2ϩ concentration, and the activation of the secretory machinery (3,4). We have also shown that sulfonylureas stimulate insulin exocytosis by directly interacting with the secretory machinery and not through closure of the plasma membrane ATP-regulated K ϩ channel (5-7). This effect may constitute part of the therapeutic benefits of sulfonylureas and contribute to their hypoglycemic action in diabetes. Although this direct effect of sulfonylureas on insulin exocytosis is now well established and suggestions for underlying molecular mechanisms have been put forward (8), the physiological relevance of these findings are still in question. This skepticism originates primarily from the difficulty in envisaging how the sulfonylureas bypass the ␤-cell plasma membrane rapidly and effectively, thereby interacting with intracellular binding sites involved in the regulation of exocytosis. Indeed, earlier studies suggested that ...

Microemulsions, comprising oil, water and a surfactant, in association with some co-surfactant, are thermodynamically stable systems. They have found applications in a large number of chemical and pharmacological processes due to their unique properties such as large interfacial area, low interfacial tension, and most importantly, the ability to solubilize and deliver hydrophobic drugs. In addition to the oral and intravenous route, they are suitable for drug delivery through the ophthalmic, vaginal, pulmonary, dental, and topical routes. This review highlights the properties and several recent developments in the use of microemulsions for medical treatment purposes including targeted drug delivery.

IntroductionInfection by intestinal parasites in childhood may be the main cause of many health-related problems in developed countries such as anemia, anorexia, loss of appetite, retarded growth and development. The aim of the present study was to assess the effect of different intestinal parasites on white adipose tissue hormones.Material and methodsEighty-one children infected by different parasites and 35 apparently healthy children were enrolled in this study. All patients and controls were subjected to clinical examination, measurement of body mass index (BMI) and laboratory examination.ResultsFor BMI percentiles, there was a significant increase in serum leptin level (p = 0.042) and a significant decrease in serum adiponectin level (p = 0.039) in uninfected children, whereas there were no significant changes in the infected group (p = 0.068 and 0.082 respectively). A significant increase in leptin and decrease in adiponectin levels were observed for E. histolytica, Strongyloides and E. histolytica and Giardia infections compared to the control group (p = 0.047, 0.035 and 0.019 for leptin, and p = 0.025, 0.038 and 0.041 for adiponectin, respectively).ConclusionsThe infection by some intestinal parasites may deregulate the secretion of leptin and adiponectin and also affect the absorption of some nutrients which can disturb the BMI and cause anorexia.