肝脏中生物流体流动的多重介质渗流模型和数值模拟

本文采用生物渗流理论，建立了肝脏内不同生物流体流动的多重介质渗流模型，采用有限元法求解这种特殊的渗流问题，根据数值计算结果揭示了肝内血液、组织液以及胆汁等的流动规律，并探讨了肝脏血流动力学的一些问题。论文将肝脏内部与生物代谢功能有关的肝血窦和窦周间隙当作两重并存的多孔介质，血液在肝血窦中，以及组织液在窦周间隙中的流动均当作渗流处理，通过Starling公式考虑了两重介质之间的流量交换，从而建立了肝血窦-窦周间隙的双重介质模型。针对肝脏胆汁分泌功能，将肝脏内密布的毛血肝管网当作多孔介质，以受静压及渗透压驱动的流体跨壁流动表示肝汁从肝细胞向毛细肝管的分泌，肝汁在毛细胆管网中的流动作为渗流处理，从而建立了肝汁分泌与输运的双重介质模型。采用有限元法求解了生物流体的双重介质渗流问题，针对非牛顿渗流和两重介质的相互作用，本文发展了一种嵌套迭代方法，即采用直接迭代求解血液在肝血窦中的非线性渗流，采用交替迭代解决双重介质渗流中由跨壁流支引起的相互流体交换，直接迭代嵌套于交替迭代中。这种算法比较有效的解决了包含非牛顿渗流的双重介质渗流问题。根据生物多孔介质中微细管系统的构筑方式以及不同微细管系统之间的联系方式，论文提出将生物多孔介质划分为分级多孔介质和多重多孔介质两种主要类型。基于多相混合物的平均化的理论，论文推导了双重多孔介质中的动量守恒方程、质量守恒方程以及相应的渗流方程，建立了双重多孔介质渗流的平均化模型。基于分级多孔介质渗流的理论，论文将脏器中的血管树按管径分为不同级别的多孔介质，各级血管中和血液流动均作为渗流处理，从而提出了计算脏器整体血流的一种渗流方法。采用这种方法，在论文提出的肝血窦 - 窦周间隙双重介质渗流流模型的基础之上，初步研究了肝脏门静脉系统的血液动力学规律。采用本文提出的肝血窦 - 窦周间隙双重介质模型和胆汁分泌 - 流动的双重介质模型，得到了血液、组织液和胆汁在肝小叶中的压力分布和速度分布，并分析了肝血窦壁的跨壁流动模式，胆汁流量的影响因素，以及窦周间隙中组织液流量与肝血窦中血液流动及肝血窦壁渗透系数等因素的关系，揭示了肝脏内血液、组织液及胆汁等生物流体流动的一般规律。

Structure and Rheology of Cationic Molecular Hydrogels of Quinuclidine Grafted Bile Salts. Influence of the Ionic Strength and Counter-Ion type

Quinuclidine grafted cationic bile salts are forming salted hydrogels. An extensive investigation of the effect of the electrolyte and counterions on the gelation has been envisaged. The special interest of the quinuclidine grafted bile salt is due to its broader experimental range of gelation to study the effect of electrolyte. Rheological features of the hydrogels are typical of enthalpic networks exhibiting a scaling law of the elastic shear modulus with the concentration (scaling exponent 2.2) modeling cellular solids in which the bending modulus is the dominant parameter. The addition of monovalent salt (NaCl) favors the formation of gels in a first range (0.00117 g cm-3 (0.02 M) < TNaCl < 0.04675 g cm-3 (0.8 M)). At larger salt concentrations, the gels become more heterogeneous with nodal zones in the micron scale. Small-angle neutron scattering experiments have been used to characterize the rigid fibers ( ≈ 68 Å) and the nodal zones. Stress sweep and creeprecovery measurements are used to relate the lack of linear viscoelastic domain to a mechanism of disentanglement of the fibers from their associations into fagots. The electrostatic interactions can be screened by addition of salt to induce a progressive evolution toward flocculation. SEM, UV absorbance, and SAXS study of the Bragg peak at large Q-values complete the investigation.

Effect of Dietary Unsaturated Oils on the Biosynthesis of Cholesterol, and on Biliary and Fecal Excretion of Cholesterol and Bile Acids in Rats1

The aim of the present work was to investigate whether the hypocholesterolemic effect of polyunsaturated oils is due to inhibition of cholesterol synthesis or increased excretion of cholesterol and bile acids through the bile and feces of animals. Separate groups of rats were fed diets containing 10% safflower oil, coconut oil or hydrogenated vegetable oils for 30 days, after which the hepatic cholesterol and bile acid synthesis and their excretion through the bile and feces were studied. As compared to the rats in the other two groups, those given the diet containing 10% safflower oil showed markedly increased rates of bile flow and excreted through their bile and feces markedly higher amounts of cholesterol and bile acids. At the same time incorporation of [1-14C] acetate and [2-14C] mevalonate into the liver cholesterol and conversion of [4-14C] cholesterol into 14C-bile acids were also higher in the same rats. In the light of these observations it has been discussed that in the animals given polyunsaturated oils, biliary and fecal loss of cholesterol and bile acids far outweighs the activation of cholesterol synthesis and thereby effectively lowers the serum cholesterol levels.

Bile Acid Derived PET-Based Cation Sensors: Molecular Structure Dependence of their Sensitivity

A number of bile acid derived photoinduced electron transfer (PET) based sensors for metal ions are prepared. A general strategy for designing the sensor with a modular nature allows for making different molecules capable of sensing different metal ions by a change in the fluorophore and receptor unit. Keeping the basic molecular structure the same, different bile acid base fluoroionophores were prepared inorder to achieve the highest sensitivity toward the metal ions. Thesensors showed similar binding constants for the same metal ion, but the degree Of fluorescence enhancement upon addition of the metal salts were different. The sensitivities of the sensors towards a certain metal were determined from the observed fluorescence enhancement upon addition of the metal salt.

Self-Assembly of Bile Steroid Analogues: Molecules, Fibers, and Networks

Structural and rheological features of a series of molecular hydrogels formed by synthetic bile salt analogues have been scrutinized. Among seven gelators, two are neutral compounds, while the others are cationic systems among which one is a tripodal steroid derivative. Despite the fact that the chemical structures are closely related, the variety of physical characteristics is extremely large in the structures of the connected fibers (either plain cylinders or ribbons), in the dynamical modes for stress relaxation of the associated SAFINs, in the scaling laws of the shear elasticity (typical of either cellular solids or fractal floc-like assemblies), in the micron-scale texture and the distribution of ordered domains (spherulites, crystallites) embedded in a random mesh, in the type of nodal zones (either crystalline-like, fiber entanglements, or bundles), in the evolution of the distribution and morphology of fibers and nodes, and in the sensitivity to added salt. SANS appears to be a suitable technique to infer all geometrical parameters defining the fibers, their interaction modes, and the volume fraction of nodes in a SAFIN. The tripodal system is particularly singular in the series and exhibits viscosity overshoots at the startup of shear flows, an “umbrella-like” molecular packing mode involving three molecules per cross section of fiber, and scattering correlation peaks revealing the ordering and overlap of 1d self-assembled polyelectrolyte species.

Fluorescent probe and NMR studies of the aggregation of bile salts in aqueous solution

The binding of the fluorescent probes 1-anilino-8-naphthalene sulfonate and dansyl cadaverine to the sodium salts of cholic, deoxycholic and dehydrocholic acids has been investigated. Enhanced probe solubilisation accompanies aggregation. Monitoring of fluorescence intensities as a function of bile salt concentration permits the detection of primary micelle formation, as well as secondary association. The transition concentrations obtained by fluorescence are in good agreement with values determined for the critical micelle concentrations, by other methods. Differences in the behaviour of cholate and deoxycholate have been noted. Fluorescence polarisation studies of 1,6-diphenyl-1,3,5-hexatriene solubilised in bile salt micelles suggest a higher microviscosity for the interior of the deoxycholate micelle as compared to cholate. 1H NMR studies of deoxycholate over the range 1–100 mg/ml suggest that micelle formation leads to a greater immobilisation of the C18 and C19 methyl groups as compared to the C21 methyl group. Well resolved 13C resonances are observed for all three steroids even at high concentration. Both fluorescence and NMR studies confirm that dehydrocholate does not aggregate.

Unlocking the potential of bile acids in synthesis, supramolecular/materials chemistry and nanoscience

The Maitra group has explored a variety of chemistry with bile acids during the past 15 years and these experiments have covered a wide variety of chemistry - asymmetric synthesis, molecular recognition, ion receptors/sensors, dendrimers, low molecular mass organo and hydrogelators, gel-nanoparticle composites, etc. Some of what excites us in this field is highlighted in this perspective article.

A bile acid derived potassium ion sensor

A chenodeoxycholic acid based K+ ion sensor has been designed using a modular approach in which a fluorophore and a cation receptor are attached to the bile acid backbone. In the absence of K+ the fluorescence of the molecule is quenched because of through-space, photo-induced electron-transfer from the aza-crown unit. Fluorescence enhancement was observed upon titration with K+ (and other alkali metal ions too). In methanol, good selectivity towards the sensing of K+ has been observed.

Adaptive dendron: A bile acid oligomer behaving as both normal and inverse micellar mimic

The normal and inverse micellar property of a bile-acid-based dendritic structure was established through dye solubilization studies in both polar and nonpolar media.

Synthesis of both enantiomers of 1-phenylethane-1,2-diol via chirality transfer from bile acid derivatives

Both enantiomers of 1-phenylethane-1,2-diol were synthesized with good to excellent enantioselectivities via selective reduction of the phenylglyoxalates derived from bile acids, followed by reductive cleavage. (C) 2000 Elsevier Science Ltd. All rights reserved.

Effects of gender, and SLCO1B1 and CYP7A1 polymorphisms on plasma bile acids in humans and the pharmacokinetics of therapeutic ursodeoxycholic acid

Bile acids are important steroid-derived molecules essential for fat absorption in the small intestine. They are produced in the liver and secreted into the bile. Bile acids are transported by bile flow to the small intestine, where they aid the digestion of lipids. Most bile acids are reabsorbed in the small intestine and return to the liver through the portal vein. The whole recycling process is referred to as the enterohepatic circulation, during which only a small amount of bile acids are removed from the body via faeces. The enterohepatic circulation of bile acids involves the delicate coordination of a number of bile acid transporters expressed in the liver and the small intestine. Organic anion transporting polypeptide 1B1 (OATP1B1), encoded by the solute carrier organic anion transporter family, member 1B1 (SLCO1B1) gene, mediates the sodium independent hepatocellular uptake of bile acids. Two common SNPs in the SLCO1B1 gene are well known to affect the transport activity of OATP1B1. Moreover, bile acid synthesis is an important elimination route for cholesterol. Cholesterol 7α-hydroxylase (CYP7A1) is the rate-limiting enzyme of bile acid production. The aim of this thesis was to investigate the effects of SLCO1B1 polymorphism on the fasting plasma levels of individual endogenous bile acids and a bile acid synthesis marker, and the pharmacokinetics of exogenously administered ursodeoxycholic acid (UDCA). Furthermore, the effects of CYP7A1 genetic polymorphism and gender on the fasting plasma concentrations of individual endogenous bile acids and the bile acid synthesis marker were evaluated. Firstly, a high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method for the determination of bile acids was developed (Study I). A retrospective study examined the effects of SLCO1B1 genetic polymorphism on the fasting plasma concentrations of individual bile acids and a bile acid synthesis marker in 65 healthy subjects (Study II). In another retrospective study with 143 healthy individuals, the effects of CYP7A1 genetic polymorphism and gender as well as SLCO1B1 polymorphism on the fasting plasma levels of individual bile acids and the bile acid synthesis marker were investigated (Study III). The effects of SLCO1B1 polymorphism on the pharmacokinetics of exogenously administered UDCA were evaluated in a prospective genotype panel study including 27 healthy volunteers (Study IV). A robust, sensitive and simple HPLC-MS/MS method was developed for the simultaneous determination of 16 individual bile acids in human plasma. The method validation parameters for all the analytes met the requirements of the FDA (Food and Drug Administration) bioanalytical guidelines. This HPLC-MS/MS method was applied in Studies II-IV. In Study II, the fasting plasma concentrations of several bile acids and the bile acid synthesis marker seemed to be affected by SLCO1B1 genetic polymorphism, but these findings were not replicated in Study III with a larger sample size. Moreover, SLCO1B1 polymorphism had no effect on the pharmacokinetic parameters of exogenously administered UDCA. Furthermore, no consistent association was observed between CYP7A1 genetic polymorphism and the fasting plasma concentrations of individual bile acids or the bile acid synthesis marker. In contrast, gender had a major effect on the fasting plasma concentrations of several bile acids and also total bile acids. In conclusion, gender, but not SLCO1B1 or CYP7A1 polymorphisms, has a major effect on the fasting plasma concentrations of individual bile acids. Moreover, the common genetic polymorphism of CYP7A1 is unlikely to influence the activity of CYP7A1 under normal physiological conditions. OATP1B1 does not play an important role in the in vivo disposition of exogenously administered UDCA.