Selectivity of Oxidizing Agents toward Axial and Equatorial Hydroxyl Groups.

A total of 16 oxidizing reagents were screened to compare their oxidation selectivities for axial and equatorial hydroxyl moieties using steroidal methyl chenodeoxycholate, methyl deoxycholate, and 4-tert-butylcyclohexanol (cis/trans 1:1 mixture). These compounds were selected for their stable chair conformations. The results of our study demonstrated that, for the oxidation of a scaffold bearing both axial and equatorial hydroxyl groups, nitroxide-radical-based reagents should be the first choice if oxidation of the equatorial hydroxyl group is needed and Stevens or Dess-Martin reagents should be the first choice for the preferential oxidation of the axial hydroxyl group.

Contactless Abdominal Fat Reduction With Selective RF™ Evaluated by Magnetic Resonance Imaging (MRI): Case Study.

BACKGROUND: Noninvasive body shaping methods seem to be an ascending part of the aesthetics market. As a result, the pressure to develop reliable methods for the collection and presentation of their results has also increased. The most used techniques currently include ultrasound measurements of fat thickness in the treated area, caliper measurements, bioimpedance-based scale measurements or circumferential tape measurements. Although these are the most used techniques, almost all of them have some limitations in reproducibility and/or accuracy. This study shows Magnetic Resonance Imaging (MRI) as the new method for the presentation of results in the body shaping industry. MATERIALS AND METHODS: Six subjects were treated by a contactless selective radiofrequency device (BTL Vanquish ME, BTL Industries Inc., Boston, MA). The MRI fat thickness was measured at the baseline and at 4-weeks following the treatment. In addition to MRI images and measurements, digital photographs and anthropometric evaluations such as weight, abdominal circumference, and caliper fat thickness measurements were recorded. Abdominal fat thickness measurements from the MRI were performed from the same slices determined by the same tissue artefacts. RESULTS: The MRI fat thickness difference between the baseline measurement and follow up visit showed an average reduction of 5.36 mm as calculated from the data of 5 subjects. One subject dropped out of study due to non-study related issues. The results were statistically significant based on the Student's T-test evaluation. CONCLUSIONS: Magnetic resonance imaging abdominal fat thickness measurements seems to be the best method for the evaluation of fat thickness reduction after non-invasive body shaping treatments. In this study, this method shows average fat thickness reduction of 5.36 mm while the weight of the subjects didn't change significantly. A large spot size measuring 1317 cm(2) (204 square inches) covers the abdomen flank to flank. The average thickness of 5.36 mm of the fat layer reduced under the applicator translates into significant cumulative circumferential reduction. The reduction was not related with dieting.

Unique effect of an electric field on a new liquid crystalline lactic acid derivative.

A new chiral lactic acid derivative is presented, exhibiting a frustrated liquid crystalline phase, namely the orthogonal twist grain boundary TGBA phase in a broad temperature interval. A unique effect is observed that the applied electric field reversibly transforms the planar TGBA texture to the homeotropic one, homogeneously dark in crossed polarizers. The transformation is analogous to the Frederiks transition known in nematics, in which switching under electric field is driven by the positive dielectric anisotropy. A similar effect is established also in the SmA phase of the racemic mixture, where the field induced transformation is irreversible. A positive dielectric anisotropy in both the chiral compound and the racemic mixture is detected up to the frequency of about 10 kHz, above this frequency the anisotropy is negative. The unusual behavior of the TGBA phase under the electric field can be explained by the specific packing of molecules within the smectic layers, resulting in a relatively high layer compressibility which lowers the energy of the structural defects and thus facilitates the structure transformation. The perfectly dark state of the studied compounds, induced by the electric field, either stable or reversible, is appealing for specific applications. The change of the sign of the dielectric anisotropy, known in nematics as the dual frequency effect, might be important for photonics such as adaptive or diffractive optics.

Thermotropic and lyotropic behaviour of new liquid-crystalline materials with different hydrophilic groups: synthesis and mesomorphic properties.

Several new calamitic liquid-crystalline (LC) materials with flexible hydrophilic chains, namely either hydroxy groups or ethylene glycol units, or both types together, have been synthesized in order to look for new functional LC materials exhibiting both, thermotropic and lyotropic behaviour. Such materials are of high potential interest for challenging issues such as the self-organization of carbon nanotubes or various nanoparticles. Thermotropic mesomorphic properties have been studied by using polarizing optical microscopy, differential scanning calorimetry and X-ray scattering. Four of these nonchiral and chiral materials exhibit nematic and chiral nematic phases, respectively. For some molecular structures, smectic phases have also been detected. A contact sample of one of the prepared compounds with diethylene glycol clearly shows the lyotropic behaviour; namely a lamellar phase was observed. The relationship between the molecular structure and mesomorphic properties of these new LCs with hydrophilic chains is discussed.

When Two Become One: Conformational Changes in FXR/RXR Heterodimers Bound to Steroidal Antagonists.

Farnesoid X receptor (FXR) is a nuclear receptor with an essential role in regulating bile acid synthesis and cholesterol homeostasis. FXR activation by agonists is explained by an αAF-2-trapping mechanism; however, antagonism mechanisms are diverse. We discuss microsecond molecular dynamics (MD) simulations investigating our recently reported FXR antagonists 2a and 2 h. We study the antagonist-induced conformational changes in the FXR ligand-binding domain, when compared to the synthetic (GW4064) or steroidal (chenodeoxycholic acid, CDCA) FXR agonists in the FXR monomer or FXR/RXR heterodimer r, and in the presence and absence of the coactivator. Our MD data suggest ligand-specific influence on conformations of different FXR-LBD regions, including the α5/α6 region, αAF-2, and α9-11. Changes in the heterodimerization interface induced by antagonists seem to be associated with αAF-2 destabilization, which prevents both co-activator and co-repressor recruitment. Our results provide new insights into the conformational behaviour of FXR, suggesting that FXR antagonism/agonism shift requires a deeper assessment than originally proposed by crystal structures.

(E)-7-Ethylidene-lithocholic Acid (7-ELCA) Is a Potent Dual Farnesoid X Receptor (FXR) Antagonist and GPBAR1 Agonist Inhibiting FXR-Induced Gene Expression in Hepatocytes and Stimulating Glucagon-like Peptide-1 Secretion From Enteroendocrine Cells.

Bile acids (BAs) are key signaling steroidal molecules that regulate glucose, lipid, and energy homeostasis via interactions with the farnesoid X receptor (FXR) and G-protein bile acid receptor 1 (GPBAR1). Extensive medicinal chemistry modifications of the BA scaffold led to the discovery of potent selective or dual FXR and GPBAR1 agonists. Herein, we discovered 7-ethylidene-lithocholic acid (7-ELCA) as a novel combined FXR antagonist/GPBAR1 agonist (IC50 = 15 µM/EC50 = 26 nM) with no off-target activation in a library of 7-alkyl substituted derivatives of BAs. 7-ELCA significantly suppressed the effect of the FXR agonist obeticholic acid in BSEP and SHP regulation in human hepatocytes. Importantly, 7-ELCA significantly stimulated the production of glucagon-like peptide-1 (GLP-1), an incretin with insulinotropic effect in postprandial glucose utilization, in intestinal enteroendocrine cells. We can suggest that 7-ELCA may be a prospective approach to the treatment of type II diabetes as the dual modulation of GPBAR1 and FXR has been supposed to be effective in the synergistic regulation of glucose homeostasis in the intestine.

3ß-Isoobeticholic acid efficiently activates the farnesoid X receptor (FXR) due to its epimerization to 3α-epimer by hepatic metabolism.

Bile acids (BAs) are important signaling molecules acting via the farnesoid X nuclear receptor (FXR) and the membrane G protein-coupled bile acid receptor 1 (GPBAR1). Besides deconjugation of BAs, the oxidoreductive enzymes of colonic bacteria and hepatocytes enable the conversion of BAs into their epimers or dehydrogenated forms. Obeticholic acid (OCA) is the first-in-class BA-derived FXR agonist approved for the treatment of primary biliary cholangitis. Herein, a library of OCA derivatives, including 7-keto, 6-ethylidene derivatives and 3ß-epimers, was synthetized and investigated in terms of interactions with FXR and GPBAR1 in transaction assays and evaluated for FXR target genes expression in human hepatocytes and C57BL/6 mice. The derivatives were further subjected to cell-free analysis employing in silico molecular docking and a TR-FRET assay. The conversion of the 3ßhydroxy epimer and its pharmacokinetics in mice were studied using LC-MS. We found that only the 3ß-hydroxy epimer of OCA (3ß-isoOCA) possesses significant activity to FXR in hepatic cells and mice. However, in a cell-free assay, 3ß-isoOCA had about 9-times lower affinity to FXR than did OCA. We observed that 3ß-isoOCA readily epimerizes to OCA in hepatocytes and murine liver. This conversion was significantly inhibited by the hydroxy-Δ5-steroid dehydrogenase inhibitor trilostane. In addition, we found that 3,7-dehydroobeticholic acid is a potent GPBAR1 agonist. We conclude that 3ß-isoOCA significantly activates FXR due to its epimerization to the more active OCA by hepatic metabolism. Other modifications as well as epimerization on the C3/C7 positions and the introduction of 6-ethylidene in the CDCA scaffold abrogate FXR agonism and alleviate GPBAR1 activation.

Acute acalculous cholecystitis with pericholecystitis in a patient with Epstein-Barr Virus infectious mononucleosis.

BACKGROUND: Acute acalculous cholecystitis is a rare complication of Epstein-Barr virus mononucleosis and involves thickening of the gallbladder wall. CASE REPORT: We describe the case of a 22-year-old woman with acute acalculous cholecystitis and pericholecystitis associated with Epstein-Barr virus primary infection. Surgical intervention was not performed, even though gallbladder perforation was suspected. The patient was treated conservatively with careful monitoring, including repeated ultrasonographic examinations. CONCLUSIONS: Epstein-Barr virus infections are usually self-limited, and surgical treatment of acute acalculous cholecystitis should only be considered when the ultrasonographic criteria persist on follow-up examinations or when they deteriorate. This is the first report of a severe course of acute acalculous cholecystitis with suspected gallbladder perforation associated with infectious mononucleosis.

Orientational and structural properties of ferroelectric liquid crystal with a broad temperature range in the SmC(*) phase by (13)C NMR, x-ray scattering and dielectric spectroscopy.

Thermotropic liquid crystalline materials laterally substituted by a methyl group on the aromatic ring of the alkoxybenzoate unit far from the chiral centre exhibit a very broad temperature range in the ferroelectric smectic C* (SmC(*)) phase on cooling (including supercooling) with a very high spontaneous polarization (∼210 nC cm(-2)) and tilt angle (∼43°) at saturation. We are presenting a detailed study of the physical properties of a ferroelectric compound, representative of this category of liquid crystals, by means of solid state (13)C-NMR, small angle x-ray scattering, dielectric spectroscopy and optical methods of the tilted SmC(*). Values of the spontaneous tilt angle measured optically are compared to those determined from the x-ray data and discussed. In addition, the viscosity has been determined in the SmC(*) phase by different experimental methods. (13)C NMR data allowed us to get information about the degree of orientational order of the SmC(*) phase and revealed the complete unwinding of the helical axis at the magnetic field of 9.4 T. This result is discussed in the framework of recent publications on the effect of the magnetic field on the supra-molecular structure of the SmC(*) phase.

Silver Nanoparticles with Liquid Crystalline Ligands Based on Lactic Acid Derivatives.

We have prepared and studied silver nanoparticles functionalized with ligands based on lactic acid derivatives. Several types of hybrid systems that differed in the size of silver nanoparticles as well as the length of surface ligands were analyzed. Transmission electron microscopy (TEM) observation provided information about the size and shape of nanoparticles and proved good homogeneity of studied systems. By dynamic light scattering (DLS) measurements, we have measured the size distribution of nanoparticle systems. Plasmonic resonance was detected at around 450 nm. For two hybrid systems, the mesomorphic behaviour has been demonstrated by x-ray measurements. The observed thermotropic liquid crystalline phases reveal lamellar character. We have proposed a model based on self-assembly of intercalated liquid crystalline ligands.

Photoinduced Changes of Surface Topography in Amorphous, Liquid-Crystalline, and Crystalline Films of Bent-Core Azobenzene-Containing Substance.

Recently, photofluidization and mass-transfer effects have gained substantial interest because of their unique abilities of photocontrolled manipulation with material structure and physicochemical properties. In this work, the surface topographies of amorphous, nematic, and crystalline films of an azobenzene-containing bent-core (banana-shaped) compound were studied using a special experimental setup combining polarizing optical microscopy and atomic force microscopy. Spin-coating or rapid cooling of the samples enabled the formation of glassy amorphous or nematic films of the substance. The effects of UV and visible-light irradiation on the surface roughness of the films were investigated. It was found that UV irradiation leads to the fast isothermal transition of nematic and crystalline phases into the isotropic phase. This effect is associated with E-Z photoisomerization of the compound accompanied by a decrease of the anisometry of the bent-core molecules. Focused polarized visible-light irradiation (457.9 nm) results in mass-transfer phenomena and induces the formation of so-called "craters" in amorphous and crystalline films of the substance. The observed photofluidization and mass-transfer processes allow glass-forming bent-core azobenzene-containing substances to be considered for the creation of promising materials with photocontrollable surface topographies. Such compounds are of principal importance for the solution of a broad range of problems related to the investigation of surface phenomena in colloid and physical chemistry, such as surface modification for chemical and catalytic reactions, predetermined morphology of surfaces and interfaces in soft matter, and chemical and biochemical sensing.

Reentrant orthogonal smectic-A phase below a tilted smectic-C phase in a chiral compound.

A reentrant orthogonal smectic-A (SmA) phase below the tilted smectic-C phase is established in a chiral liquid crystalline compound. The temperature evolution of the layer spacing confirms monolayer structure in both SmA phases, the upper SmA as well as the reentrant SmA phase. The reentrancy of the SmA phase is explained on the basis of the mean field free energy taking into account nonmonotoneous temperature dependence of the lowest term coefficient.

Binary mixtures of liquid crystalline compounds with a reentrant smectic-A* phase.

Binary mixtures of chiral liquid crystalline homologs have been studied. One compound designated 9ZBL exhibited reentrancy of a paraelectric smectic-A* phase, SmA*(RE), below the ferroelectric SmC* phase in the SmA*-SmC*-SmA*RE phase sequence. Stabilization of the SmA(RE) phase is established from studying binary mixtures of 9ZBL with its neighboring homologs 8ZBL and 10ZBL. Compound 8ZBL exhibits only SmA* phase in a wide temperature range and for 10ZBL the SmA*-SmC* phase sequence is observed on cooling. X-ray studies, dielectric spectroscopy, polarization, and tilt angle measurements have been carried out to characterize studied materials. For binary mixtures 9ZBL-10ZBL the reentrant SmA_(RE*) phase is observed for all studied concentrations. For binary mixtures 9ZBL-8ZBL a very small amount of 8ZBL (up to 0.5 mole %) causes disappearance of the SmC* phase. Nevertheless, a small anomaly in the temperature dependencies of the layer spacing, d(T), accompanied by a significant decrease in diffracted x-ray intensity occurs within the SmA* phase for mixtures containing up to 20 mole % of 8ZBL. This anomaly is evidence of the existence of a boundary between the SmA* and SmA(RE*) phases, thus proving their different nature.