Effect of humidity on the disintegrant property of α-cellulose,Part II: A technical note

Conclusion  The summary is that the high humidity impaired the disintegrant property of α-cellulose in all 3 tablets tested. Tablets of aspirin, which is the more hygroscopic drug, were also more sensitive to the humidity effect, while tablets of chloroquine phosphate, which is a water-soluble drug, were the least sensitive to the humidity effect. The results permit the conclusion that moisture uptake with subsequent gelling of the α-cellulose is the mechanism of impairment of its disintegrant property. The tablets would not normally be stored under an RH as high as 100%, nevertheless, the results of the accelerated stability study have underscored the need to protect tablets containing α-cellulose as disintegrant from moisture. Published: August 10, 2005     

An extended aqueous solvation model based on atom-weighted solvent accessible surface areas: SAWSA v2.0 model

A new method is proposed for calculating aqueous solvation free energy based on atom-weighted solvent accessible surface areas. The method, SAWSA v2.0, gives the aqueous solvation free energy by summing the contributions of component atoms and a correction factor. We applied two different sets of atom typing rules and fitting processes for small organic molecules and proteins, respectively. For small organic molecules, the model classified the atoms in organic molecules into 65 basic types and additionally. For small organic molecules we proposed a correction factor of hydrophobic carbon to account for the aggregation of hydrocarbons and compounds with long hydrophobic aliphatic chains. The contributions for each atom type and correction factor were derived by multivariate regression analysis of 379 neutral molecules and 39 ions with known experimental aqueous solvation free energies. Based on the new atom typing rules, the correlation coefficient (r) for fitting the whole neutral organic molecules is 0.984, and the absolute mean error is 0.40 kcal mol^–1, which is much better than those of the model proposed by Wang et al. and the SAWSA model previously proposed by us. Furthermore, the SAWSA v2.0 model was compared with the simple atom-additive model based on the number of atom types (NA). The calculated results show that for small organic molecules, the predictions from the SAWSA v2.0 model are slightly better than those from the atom-additive model based on NA. However, for macromolecules such as proteins, due to the connection between their molecular conformation and their molecular surface area, the atom-additive model based on the number of atom types has little predictive power. In order to investigate the predictive power of our model, a systematic comparison was performed on seven solvation models including SAWSA v2.0, GB/SA_1, GB/SA_2, PB/SA_1, PB/SA_2, AM1/SM5.2R and SM5.0R. The results showed that for organic molecules the SAWSA v2.0 model is better than the other six solvation models. For proteins, the model classified the atoms into 20 basic types and the predicted aqueous free energies of solvation by PB/SA were used for fitting. The solvation model based on the new parameters was employed to predict the solvation free energies of 38 proteins. The predicted values from our model were in good agreement with those from the PB/SA model and were much better than those given by the other four models developed for proteins.Figure The definition of hydrophobic carbons. Here CA, CB and CD are three carbon atoms; X represents a heteroatom. According to our definition, CB is a hydrophobic carbon, CA is not a hydrophobic carbon because a heteroatom is within four atoms and CD is not a hydrophobic carbon because CD is sp²- hydridized and in a six-member ring.Electronic Supplementary Material Supplementary material is available for this article at     

Interaction and structural study of kinin peptide bradykinin and ganglioside monosialylated 1 micelle

Partitioning of small proteins and peptides from the aqueous to membrane phase is often coupled with folding. In this work we examine the binding and folding of the kinin peptide, bradykinin (BK), in the presence of the ganglioside monosialylated 1 (GM1) micelle. Using two-dimensional NMR techniques, we have shown that at low concentration, GM1 micelle is able to induce a turn conformation to BK. A pulsed-field gradient diffusion NMR study indicated that the peptide partitions into the GM1 micelle with a DeltaG(part) of -3.14 +/- 0.03 kcal/mol. A saturation transfer difference (STD) NMR study indicated that the binding is mostly through hydrophobic residues.     

Conformation of peptides constructed from achiral amino acid residues Aib and DeltaZPhe: computational study of the effect of L/D- Leu at terminal positions

Conformational studies of the peptides constructed from achiral amino acid residues Aib and Delta(Z)Phe (I) Ac-Aib-Delta(Z)Phe-NHMe (II), and Ac-(Aib-Delta(Z)Phe)(3)-NHMe; peptides III-VI having L-Leu or D-Leu at either the N- or the C-terminal position and of peptides VII-X having Leu residues in different enantiomeric combinations at both the N- and the C-terminal positions in peptide II have been studied to design the peptide with the required helical sense. Peptide II, as expected, adopts degenerate left- and right-handed helical structures. It has been shown that the peptides IV and VI having D-Leu at either the N or the C terminus can be realized in the right-handed helical structure with the phi,psi values of -20 degrees and -60 degrees for the Aib/Delta(Z)Phe residues. L-Leu and D- Leu at both the terminals in peptides VII and VIII, respectively, have hardly any effect as both the left- and the right-handed structures are found to be degenerate. Peptides III and IX can be realized in right- and left-handed helical structures, respectively, in solvents of low polarity whereas peptides V and X are predicted to be in the right-handed helical structures stabilized by carbonyl-carbonyl interactions without the formation of hydrogen bonds. The conformational states with the phi,psi values of 0 degrees and -85 degrees in peptide V are characterized by rise per residue of 2.03 A, rotation per residue of 117.5 degrees , and 3.06 residues per turn. In all peptides having Leu residue at the N terminus, the methyl moiety of the acetyl group is involved in the CH/pi interactions with the Cepsilon--Cdelta edge of the aromatic ring of Delta(Z)Phe (3) and the amino group NH of Delta(Z)Phe is involved in the NH/pi interactions with its own aromatic ring. The CH(3) groups of the Aib residues are also involved in CH/pi interactions with the i + 1th and i + 3th Delta(Z)Phe's aromatic side chains.     

QM/MM study of D-fructose in aqueous solution

The QM/MM molecular dynamics methodology was applied to the study of the two main D-fructose tautomers present in aqueous solution, beta-D-fructofuranose and beta-D-fructopyranose. The solute was treated at the AM1 semi-empirical level, and for the solvent water molecules we used the TIP3P potential. We analyzed the structure of the water molecules around the hydroxyl groups to explain the differences in sweet taste between the two tautomers.     

Structural and serological characterization of the O-chain polysaccharide of Aeromonas salmonicida strains A449, 80204 and 80204-1

The O-chain polysaccharide (O-PS) of Aeromonas salmonicida was studied by a combination of compositional, methylation, CE-ESMS and one- and two-dimensional NMR analyses. It was found to be a branched polymer of trisaccharide-repeating units composed of L-rhamnose (Rha), D-glucose (Glc), 2-acetamido-2-deoxy-D-mannose (ManNAc) and O-acetyl group (OAc) and having the following structure: CE-ESMS analysis of A. salmonicida cells from strains A449, 80204 and 80204-1 grown under different conditions confirmed that the O-PS structure was conserved. ELISA-based serological study with native LPS-specific antisera performed on the native O-PS and its O-deacetylated and periodate-oxidized derivatives confirmed the importance of the O-PS backbone structure as an immunodominant determinant.     

Hypercalcemia produced by parathyroid hormone suppresses experimental autoimmune encephalomyelitis in female but not male mice

Besides its role in regulating serum levels of calcium and phosphorus, 1alpha, 25-dihydroxyvitamin D3 (1,25-(OH)2D3) has potent effects on the immune system and suppresses disease in several animal models of autoimmune disorders including experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis. While the amount of 1,25-(OH)2D3 needed to prevent EAE is dependent on the gender of the mouse and amount of calcium available in the diet, the minimum levels of 1,25-(OH)2D3 sufficient to prevent disease cause hypercalcemia. To test if hypercalcemia independent of high levels of 1,25-(OH)2D3 can suppress EAE, we used a 25-hydroxyvitamin D3-1alpha-hydroxylase (1alpha-hydroxylase) knockout mouse strain. Because these 1alpha-hydroxylase knockout mice lack the parathyroid hormone (PTH)-regulated enzyme that synthesizes 1,25-(OH)2D3, hypercalcemia from increased bone turnover was created by continuous administration of PTH without changing the circulating levels of 1,25-(OH)2D3. This PTH-mediated hypercalcemia generated after EAE induction prevented disease in female mice but not male mice. When hypercalcemia was prevented by diet manipulation, PTH administration no longer prevented EAE. We conclude that hypercalcemia is able to prevent EAE after disease induction in female mice.     

17-beta-estradiol activates maxi-K channels through a non-genomic pathway in human breast cancer cells

We have investigated the acute effects of 17-beta-estradiol (E2) on K+ channels in MCF-7 breast epithelial cancer cells. E2 induced a rapid and irreversible augmentation of the K+ current for all membrane potentials superior to -25 mV. The effect of E2 was sensitive to Iberiotoxin, Charybdotoxin and TEA and can be elicited in the presence of the anti-estrogen ICI 182780 or be mimicked by the membrane impermeant form E2/BSA. Furthermore, E2/BSA was able to stimulate cell proliferation in a maxi-K inhibitors-sensitive manner. Thus, these results permit us to identify the maxi-K channel as the molecular target of E2 that regulates cell proliferation independently of the estrogen receptor.     

Similarities and differences in the transcriptional regulation of the leptin gene promoter in gastric and adipose cells

The stomach was reported to synthesize and secrete leptin mainly in the gastric lumen. Gastric leptin release is markedly increased after food intake, by vagal cholinergic stimulation and by cholecystokinin and secretin. Here we show that human gastric MKN-74 cells produce leptin that increases upon challenge with cholecystokinin, insulin, glucocorticoids and all-trans retinoic acid through activation of the leptin gene promoter. In addition, we demonstrate that forskolin and BRL37344 which increased cAMP levels, fail to affect the activity of leptin gene promoter in MKN74 expressing beta(3)-adrenoceptor cells but, induce a 2-fold decrease in this activity in adipose 3T3-L1 cells. These data described for the first time, similarities and more interestingly, differences in the regulation of the leptin gene promoter in gastric cells as compared to adipocytes.