Bio-inspired supramolecular materials by orthogonal self-assembly of hydrogelators and phospholipids.

The orthogonal self-assembly of multiple components is a powerful strategy towards the formation of complex biomimetic architectures, but so far the rules for designing such systems are unclear. Here we show how to identify orthogonal self-assembly at the supramolecular level and describe guidelines to achieve self-sorting in self-assembled mixed systems. By investigating multicomponent self-assembled systems consisting of low molecular weight gelators and phospholipids, both at a molecular and a supramolecular level, we found that orthogonal self-assembly can only take place if the entities assemble via a strong and distinct set of interactions. The resulting supramolecular architectures consist of fibrillar networks that coexist with liposomes and thereby provide additional levels of compartmentalization and enhanced stability as compared to self-assembled systems of gelators or phospholipids alone.

Interaction of melittin with negatively charged phospholipids: consequences for lipid organization.

A characterization of the structural alterations induced by melittin in model-membranes of dioleoylphosphatidic acid and egg phosphatidylglycerol is presented, based on the use of 31P-NMR, freeze-fracture electron microscopy and small angle X-ray scattering. In accordance with earlier findings on the cardiolipin-melittin system, melittin is found to have an inverted phase inducing effect on these negatively charged lipids, in contrast to the influence on zwitterionic phospholipids. In phosphatidic acid this is expressed in the formation of an HII phase; in phosphatidylglycerol a less ordered, non-lamellar structure with low water content is adopted.

Cushing's disease and hypertension: in vivo and in vitro study of the role of the renin-angiotensin-aldosterone system and effects of medical therapy.

OBJECTIVE/METHODS: Cushing's disease (CD) is often accompanied by hypertension. CD can be treated surgically and, given the expression of somatostatin subtype 5 and dopamine 2 receptors by corticotroph pituitary adenomas, pharmacologically. Indeed, we recently observed that stepwise medical combination therapy with the somatostatin-analog pasireotide, the dopamine-agonist cabergoline, and ketoconazole (which directly suppresses steroidogenesis) biochemically controlled CD patients and lowered their blood pressure after 80 days. Glucocorticoids (GC) modulate the renin-angiotensin-aldosterone system (RAAS) among others by increasing hepatic angiotensinogen expression and stimulating mineralocorticoid receptors (MR). This study therefore evaluated plasma RAAS components in CD patients before and after drug therapy. In addition, we studied whether cabergoline/pasireotide have direct relaxant effects in angiotensin II (Ang II)-constricted iliac arteries of spontaneously hypertensive rats, with and without concomitant GR/MR stimulation with dexamethasone or hydrocortisone. RESULTS: Baseline concentrations of angiotensinogen were elevated, while renin and aldosterone were low and suppressed, respectively, even in patients treated with RAAS-blockers. This pattern did not change after 80 days of treatment, despite blood pressure normalization, nor after 4 years of remission. In the presence of dexamethasone, pasireotide inhibited Ang II-mediated vasoconstriction. CONCLUSIONS: The low plasma renin concentrations, even under RAAS blockade, in CD may be the consequence of increased GC-mediated MR stimulation and/or the elevated angiotensinogen levels in such patients. The lack of change in RAAS-parameters despite blood pressure and cortisol normalization suggests persisting consequences of long-term exposure to cortisol excess. Finally, pasireotide may have a direct vasodilating effect contributing to blood pressure lowering.

Ring closure dynamics of BTE-based photochromic switches: perfluoro- versus perhydrocyclopentene derivatives.

The switching behavior of 1,2-bis(5-phenyl-2-methylthien-3-yl)perfluorocyclopentene and its nonfluorinated (perhydro) analogue are compared. For both molecules, the dynamics after optical excitation can be separated into three regimes: preswiching due to excited state mixing; the ring closure itself; postswitching related to vibrational cooling. The fluorinated version switches faster than its nonfluorinated analogue by about a factor of 4.7. This is explained by electronic level shifts near the crossing region between the S(1) and S(0) potential energy surfaces. In the nonfluorinated molecule the various levels involved in the switching have well-separated transition frequencies, which allow for a clear interpretation of experimental data. Thus, the fluorinated molecule makes a better (more efficient and faster) switch, but the nonfluorinated molecule provides a better model system for fundamental studies.

Melittin-induced changes of the macroscopic structure of phosphatidylethanolamines.

The binding of melittin to phosphatidylethanolamine model systems and its influence on the supramolecular organization of the lipid were investigated with binding assays, differential scanning calorimetry, 31P NMR, freeze-fracture electron microscopy, and small-angle X-ray scattering. The results are compared with binding to an analogous phosphatidylcholine and structural consequences thereof. Melittin binds with similar affinity to both lipid types in the liquid-crystalline state; at gel-phase temperatures, in contrast, interaction with phosphatidylethanolamine is much weaker and does not lead to the bilayer fragmentation observed for phosphatidylcholines. With regard to phosphatidylethanolamine polymorphism, it is shown that melittin acts as an inhibitor of HII-phase formation and as a stabilizer of the bilayer organization. It is demonstrated that the remarkable variety of effects of melittin on the polymorphism of different membrane phospholipids can be understood in a relatively simple concept, taking into account the relative position and the shape of the interacting components.