Wen-Hua Chen

Loosening and Reorganization of Fluid Phospholipid Bilayers by Chloroform

The mixing behavior of an exchangeable phospholipid (A) with an exchangeable sterol (B) in host bilayers made from 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) containing varying concentrations of cholesterol has been examined via the nearest-neighbor recognition method. At low sterol concentrations (i.e., 2.5 mol %), the mixing between A and B is close to ideal. Incremental increases in the sterol concentration to 40 mol % led to net increases in the affinity between A and B. Similar mixing experiments that were carried out in the presence of chloroform showed a leveling effect, where moderate sterol-phospholipid affinity was observed in all cases. These results, together with the fact that the number of chloroform molecules that are absorbed per phospholipid is essentially constant and independent of the sterol content, support a model in which chloroform favors solvation of the phospholipids and a common membrane state is produced. Fluorescence measurements and Raman spectra have also shown that chloroform significantly loosens both cholesterol-poor and cholesterol-rich membranes made from DPPC. In a broader context, these results suggest a fundamentally new mechanism of anesthesia, where the anesthetic, by solvating the lipid components, profoundly changes the lateral organization of the lipid framework.

A fine line between molecular umbrella transport and ionophoric activity.

A persulfated molecular umbrella derived from one spermine, four lysine, and eight deoxycholic acid molecules was found to exhibit ionophoric activity, as shown by pH discharge and Na(+) and Cl(-) transport experiments. In sharp contrast, a moderately more hydrophilic analogue derived from cholic acid showed no such ionophoric activity. Both molecular umbrellas crossed liposomal membranes by passive transport with experimental rates that were similar. These findings show how the interactions between such amphomorphic molecules and phospholipid bilayers are a sensitive function of the umbrellas hydrophilic/lipophilic balance (HLB). They also raise the possibility of exploiting molecular umbrellas in fundamentally new ways.

Oxysterol-Induced Rearrangement of the Liquid-Ordered Phase: A Possible Link to Alzheimer’s Disease?

Nearest-neighbor recognition measurements have been made for an exchangeable phospholipid (A) interacting with an exchangeable form of cholesterol (B) in host membranes derived from 1, 2-dipalmitoyl-sn-glycero-3-phosphocholine and varying concentrations of cholesterol, 7beta-hydroxycholesterol (7beta-OH), and 25-hydroxycholesterol (25-OH). Whereas partial replacement of cholesterol with 7beta-OH strengthens the association between A and B, a similar substitution with 25-OH weakens this association. A model that accounts for this dichotomy, and the possible relevance of these findings to the cytotoxicity of 7beta-OH and to Alzheimers disease are briefly discussed.

Reduced sterol-phospholipid recognition in curved fluid bilayers.

Nearest-neighbor recognition experiments have been carried out in fluid liposomal membranes made from 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) and cholesterol using exchangeable dimers derived from 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine and cholesterol. In cholesterol-rich bilayers, the association between these two exchangeable lipids was reduced as the curvature of the membrane increases; that is, when the diameter of the liposomes was below ca. 200 nm. In sharp contrast, the mixing of these exchangeable lipids was close to random in the cholesterol-poor membranes, regardless of their curvature. The biological implications of these findings are briefly discussed.

Phospholipid Complexation of General Anesthetics in Fluid Bilayers

A nearest-neighbor recognition analysis has been performed in cholesterol-rich and cholesterol-poor liposomes derived from 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) in the presence of varying concentrations of chloroform. This analysis has yielded a fundamentally new, molecular-level view of the interaction of general anesthetics with lipid bilayers, which may be relevant to their biological action; that is, DPPC forms 1:1 complexes with CHCl(3) in both membranes in the fluid bilayer state.

Towards Squalamine Mimics: Synthesis and Antibacterial Activities of Head‐to‐Tail Dimeric SterolPolyamine Conjugates

Four dimeric sterolpolyamine conjugates have been synthesized from the homo‐ and hetero‐connection of monomeric sterolpolyamine analogs in a head‐to‐tail manner. These dimeric conjugates show strong antibacterial activity against a broad spectrum of Gram‐positive bacteria, whereas their corresponding activities against Gram‐negative bacteria are relatively moderate. Though no significant difference was observed in the activities of these conjugates, cholic acid‐containing dimeric conjugates generally exhibit higher activities than the corresponding deoxycholic acid‐derived analogs. This is in contrast to the finding that a monomeric deoxycholic acid‐spermine conjugate was more active than the corresponding cholic acid‐derived analog.