No description available.

No description available.

No description available.

No description available.

Yes / We report results of atomistic molecular dynamics simulations of an industrially-relevant, exemplar triacylglycerol (TAG), namely tristearin (TS), under aqueous conditions, at different temperatures and in the presence of an anionic surfactant, sodium dodecylbenzene sulphonate (SDBS). We predict the TS bilayers to be stable and in a gel phase at temperatures of 350 K and below. At 370 K the lipid bilayer was able to melt, but does not feature a stable liquid–crystalline phase bilayer at this elevated temperature. We also predict the structural characteristics of TS bilayers in the presence of SDBS molecules under aqueous conditions, where surfactant molecules are found to spontaneously insert into the TS bilayers. We model TS bilayers containing different amounts of SDBS, with the presence of SDBS imparting only a moderate effect on the structure of the system. Our study represents the first step in applying atomistic molecular dynamics simulations to the investigation of TAG-aqueous interfaces. Our results suggest that the CHARMM36 force-field appears suitable for the simulation of such systems, although the phase behaviour of the system may be shifted to lower temperatures than is the case for the actual system. Our findings provide a foundation for further simulation studies of the TS-aqueous interface. / veski

Abstract not available

Cellular energy transduction processes are often driven by transmembrane ion gradients, and a number of artificial membrane systems have been developed that allow for chemically or light-induced transport of ions across lipid bilayers. These liposomal architectures, however, are not readily interfaced to a solid-state transducer. A significant step toward this goal is described here by assessing the possibility of coupling a lipid bilayer directly to a transducer to form a stable uniform film using hybrid bilayer membranes (HBMs).Although the surface attachment of self-assembled monolayer increases the robustness of the lipid assembly, HBMs cannot maintain film uniformity under harsher conditions due to the absence of strong lipid-lipid interactions. Therefore, HBMs were prepared and characterized using a cross-linking polymerizable lipid, bis-SorbPC. Several parameters relating to lipid deposition and film stabilization through polymerization were examined. Film characterization strongly suggests that polymerization of bis-SorbPC stabilizes the HBM such that its structure is largely preserved even after the dehydration process. This work suggests that network formation in the upper monolayer is not enough to prevent oligomer desorption, intermonolayer covalent linking is also a prerequisite in making uniform, defect-free planar supported lipid assemblies.Some of the challenges associated with the application of lipids involve the creation of supported bilayers that are stable to chemical and physical disruptions, yet retain their ion barrier properties, and allow transmembrane ion transport by lipid-soluble shuttles. Polymerized lipid films provide the stability required for these structures, but permeability properties of cations across poly(lipid) membranes are not known. Therefore, convenient liposome-based proton and calcium permeability assays were developed. These assays were applied to various poly(lipid) compositions.In addition, three novel sorbyl-substituted head group polymerizable lipids, which have been synthesized based on a strategy that head group polymerization would minimally perturb the characteristic ion impermeability of the membrane, were evaluated for their lipid characteristics and ability to form polymers. None of these compounds forms vesicles by itself. Therefore, attempts were made to form mixed vesicles with other fluid lipids. The miscibility of the mixed monolayers was assessed using Langmuir isotherms.

The thesis entitled “Evolution of New Lipids and Molecular Gelators: Syntheses, Aggregation Properties and Applications” elucidates the design, synthesis, aggregation properties and application of new lipids based on α-tocopheryl backbone and also with triazacyclononane (TACN) moiety. This thesis also elucidates the synthesis and aggregation properties of molecular gelators based on pyrene-pentapeptide and naphthalene diimide (NDI) moiety. The work has been divided into five chapters. Chapter 1: Introduction: Self-assembled Molecular Aggregates and their Potential Applications This chapter describes the importance of different self-assemble mainly lipids and molecular gelator. Lipids mediated gene delivery, drug delivery and metal ion induced interaction are discussed. For liposomal gene delivery here we mainly describe example of cationic gemini lipids. This chapter also gives a comprehensive account of the research towards the development of novel liposomal drug delivery containing tocopheryl backbone. It also includes the utilization of liposome which could coordinate with metal ions and their interaction with different biological analyte. Here we also discuss a wide range of molecular gelator mainly based on NDI and amino acid or peptide. Chapter 2A: Physicochemical Characterization of Bilayer Membranes Derived from (±) α-Tocopherol Based Gemini Lipids and their Interaction with plasmid-DNA and Phosphatidylcholine Bilayers In this sub-chapter we discuss the membrane formation and aggregation properties of a series of (±) α-tocopherol based cationic gemini lipids (Figure 1) varying polymethylene spacer length (TnS; n = 3, 4, 5, 6, 8 and 12) are studied extensively while comparing with corresponding properties of monomeric counterpart (TM). Liposomal suspensions of all cationic lipids are characterized by atomic force microscopy (AFM), transmission electron microscopy (TEM), dynamic light scattering (DLS), zeta potential measurements and small angle x-ray diffraction studies. Aggregation properties of the gemini lipids are highly dependent on the spacer length and were significantly distinct from that of monomeric lipid (TM). Figure 1. Molecular structures of (±) α-tocopherol based cationic monomeric and six gemini lipids that differ in polymethylene spacer length. Stable monolayer formation at air water interface formation of each amphiphile is studied by Langmuir film balance technique. Interaction of liposome with plasmid DNA is studied by ethidium bromide (EB) intercalation assay. Micellar sodium dodecyl sulphate (SDS) mediated release of the plasmid DNA from various pre-formed lipoplex is also studied. Structural transformation of pDNA upon complexation with liposome is characterized by circular dichroism (CD) spectroscopy. Interaction of all tocopheryl lipids with a model phospholipid, L-α-dipalmitoyl phosphatidylcholine (DPPC) derived vesicles is thoroughly examined by differential scanning calorimetry (DSC) and DPH fluorescence anisotropy measurements. Succinctly, we perform a detailed physicochemical characterization on cationic monomeric and gemini lipids bearing tocopherol as their hydrophobic backbone. Chapter 2B: Physicochemical Characterization of Bilayer Membranes Derived from (±) α-Tocopherol Based Gemini Lipids Containing Hydroxyethyl Functionality in the Headgroups and their Interaction with plasmid-DNA and Phosphatidylcholine Bilayers This sub-chapter describes the synthesis and aggregation properties of series of tocopheryl-based monomeric and gemini cationic lipids with hydroxyethyl functionality (Figure 2) in the headgroup region. Gemini lipids of this given series differ in their polymethylene spacer -(CH2)n- chain lengths between cationic headgroups. All monomeric and gemini lipids are found to generate stable suspensions in aqueous media. Average hydrodynamic diameter and surface charge of liposome are characterized by DLS and zeta potential measurements. Atomic force microscopy and transmission electron microscopic studies show that all lipids form vesicular Figure 2. Molecular structures of (±) α-tocopherol based cationic monomeric and five new lipids with hydroxyethyl functionality in the headgroups that differ in polymethylene spacer length aggregates in aqueous media. XRD studies with the cast films of lipids reveal interdigitated bilayer arrangement of liposome. pDNA binding and release studies show that the interactions between gemini lipids and DNA depend upon the nature of head group as well as the length of the spacer between cationic head groups. Circular Dichroism (CD) spectra of lipoplex are measured to characterize structural transformation of pDNA upon complexation with liposome. DPH anisotropy and DSC studies of the DPPC-cationic lipid co-aggregates show that ~20 mol-% of of the tocopheryl gemini lipids is enough to abolish phase transition of DPPC membranes whereas more than 20 mol-% is required in case of their monomeric counterparts. Furthermore thermotropic properties of co-aggregates depend upon the length of the spacer of gemini lipid included in the mixture. Chapter 2C: Transfection Efficacies of α-Tocopherol Based Cationic Gemini Lipids with Hydroxyethyl Containing Headgroups. In this sub-chapter, we demonstrate transfection efficiency of five α-tocopheryl gemini lipid with hydroxyethyl containing headgroups (Figure 3). Co-liposomal formulations with helper lipid 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) form highly stable formulations in water. Co-liposomal formulations with high molar ratio of DOPE (1.5:1 and 2:1) show higher transfection efficiency than liposome with low DOPE content liposome. Co-liposome of gemini lipids with longer spacer (n = 8 and 12) have higher level of luciferase expression in HepG2 cell line. In A549 and MCF-7 cell lines also co-liposomes of TH8S (2:1) are proved to be better than other co-liposome. N/P ratios of highest transfection are 1-1.5. These formulations are more potent than L2K in all three cancer cell line. The comparison with gemini lipid (T8T) without Figure 3. Molecular structures of (±) α-tocopherol based cationic gemini lipids that differ in polymethylene spacer length and helper lipid DOPE. hydroxylethyl group also proves the importance of hydroxyethyl functionalities. High serum stability of DOPE-gemini lipid formulation is attributed to tocopherol backbone and also hydroxyethyl functionalities. Circular dichroism data also show that lipoplex of DOPE-TH8S (2:1) have different conformation than the other. Relatively moderate binding efficiency and easy release of pDNA is also observed with DOPE-TH8S (2:1) in the EB-displacement assay which could be plausible reason for high transfection efficiency. Chapter 2D: Reduction Responsive Nanoliposomes of α-Tocopheryl-Lipoic Acid Conjugate for Efficacious Drug Delivery to Sensitive and Resistant Cancer Cells In this sub-chapter, we present lipid conjugates derived from biologically relevant molecules, i.e., tocopherol and lipoic acid (Figure 4). These conjugates (TL1 and TL2) are able to form stable nanoliposomes (~100 nm) that respond to the reducing environment of cells as shown by the treatments of 1,4-Dithiothreitol (DTT) and Glutathione (GSH). Figure 4. Molecular structures of tocopheryl-lipoic acid conjugates, TL1 and TL2 Nanoliposomes could efficiently load the drug (DOX) molecules and release them in response to the stimulus. Nanoliposomes are stable enough in the presence of serum and could deliver DOX inside drug sensitive and drug resistant cells in an efficient manner that is even better than the drug alone treatments as shown by means of flow cytometry and confocal microscopy analysis. DOX loaded nanoliposomal formulations show relatively less cell viability counts than those drug alone treatments. Chapter 3A: Interaction of Nickel (II) and mida ole it Triazacyclononane Modified Chelator Amphiphiles: A Potential Substrate for Immobilization of His-tag Protein on Hydrophilic Surface This sub-chapter describes two chelator amphiphiles based on 1, 4, 7-traiazaclonone (TACN) (Figure 5). These compounds could bind efficiently Ni2+ ion. Self-assemble of these amphiphiles form vesicular aggregates. Their packing properties of these amphiphiles are influence by Ni2+ and imidazole. Also influence of Ni2+ and imidazole in Langmuir monolayer isotherm of these amphiphiles at air-water interface are also studied. Figure 5. Molecular structures of TACNA chelator amphiphiles. These studies show the newly synthesized amphiphiles could immobilize histidine tagged protein on both bilayer and monolayer surface. One of these compounds with Ni2+ (C16TACNA-Ni2+) is used to transfer a His-tagged protein nucleolin on hydrophilicobic glass surface by Langmuir-Blodgett transfer technique. So, these compounds with Ni2+ could be very useful to attach different His-tagged protein or polypeptide of interest on the bilayer (liposome) or monolayer surface. Chapter 3B: Supramolecular Hosts for Enhancing the Selectivity of TACN Based Probes towards Copper (II): Differential Output Signals for Cysteine and Histidine In this sub-chapter, we have developed a new amphipathic probe compound 1 having TACN as the binding site and dansyl as signaling moiety (Figure 6). As TACN is known for its’ unspecific interaction with multiple ions, the probe shows response with most of the transition metal ions. However, incorporation into different supramolecular hosts (like micelle and vesicles) drastically improves the selectivity of compound 1 towards Cu2+ (diminution of bright green fluorescence) in water. Then we Figure 6. Molecular structures of dansylated TACN chelator amphiphiles. have also employed the Cu2+ complex of compound 1 for selective estimation of amino acids. Addition of cysteine regains the green emission of compound while histidine exhibits blue intense emission upon formation of ternary conjugate. Chapter 4: Transforming a β-Sheet Pyrenylated-VPGKG Sequence into pH Tolerent, Thixotropic Hydrogel by Arene-Perfluoroarene Interactions and Visualized Sensing of Calcium (II) Ion In this chapter we discuss self-assembly studies of a novel thermoresponsive, lipidated, pyrene-appended peptide, PyP (Figure 7). Size of the vesicular aggregates of the β-sheet forming peptide, PyP, strongly depends on the temperature of the solution in water. Further pyrene-octafluoronaphthalene (OFN) pair has been used as supramolecular synthon to induce hydrogelation of PyP in presence of equimolar amount of OFN via complementary quadrupole-quadrupole interactions. The gel shows excellent pH tolerant as well as thixotropic behavior. Detailed studies suggested the lamellar packing of the gelator in a right-handed helical fashion yielded vesicular aggregates. The sticky vesicles form gel via inter- Figure 7. Molecular structure of the Pyrenylated-VPGKG peptide (PyP) and octafluoronapthalene (OFN). Ca2+ ion reinforces the mechanical strength and also reduces the critical gelator concentration of the native gel through coordination with the free -COO- group of the gelator. Therefore, this present system could be used as a visualized sensor of Ca2+ ion. Chapter 5: First Report of Naphthalenediimide Based Metallo(organo)gel In this chapter, we have demonstrated synthesis of a novel asymmetric bolaamphiphilic (Figure 8). NDI derivative is capable of self assemble into stable gel in EtOH. Detailed studies reveal the gelator molecule of 1 adopt a parallel alignment in the lamellae during self-aggregation as nanoscopic spherical assemblies. In addition, dried gel of 1 shows nematic liquid crystalline phase. Further, we synthesize a novel metal-ligand discrete complex 2 in a nearly quantitative yield by reacting equimolar amount of 1 and PdCl2(PhCN)2. Figure 8. NDI derivative, 1, and its discrete metal complex 2. Complex 2 has been found to yield stable gel in dichloromethane (DCM) or chloroform (CHCl3) through the formation of high aspect ratio fibers. ROESY NMR experiment of Complex 2 has been found to yield stable gel in dichloromethane (DCM) or chloroform (CHCl3) through the formation of high aspect ratio fibers. ROESY NMR experiment of

Call number: LD2668 .T4 1985 A28 / Master of Science

Niacin has been in clinical use for over 50 years and was the first drug shown in a randomized trial to improve outcomes after MI, but substantial uncertainty remains about its efficacy and safety in the context of current standard medical therapy. This thesis explores the biochemical efficacy, tolerability and safety of extended release (ER) niacin/laropiprant in the large, randomized HPS2-THRIVE trial. Laropiprant is a prostaglandin D₂ receptor (DP1) antagonist which reduces the main adverse effect of niacin, namely “flushing” (an unpleasant cutaneous vasodilation) that makes a large trial of niacin practicable. ER niacin/laropiprant increases high density lipoprotein cholesterol (HDL-C) and apolipoprotein A1, and reduces low density lipoprotein cholesterol (LDL-C), apolipoprotein B, triglycerides and lipoprotein (a), consistent with previous studies of ER niacin. The reasons for stopping ER niacin/laropiprant reflected the known adverse effect profile of ER niacin, although unlike previous trials flushing was not the most frequent reason for stopping. Skin (pruritus and rash), gastrointestinal (nausea, pain and diarrhoea) and diabetes-related (hyperglycaemia) adverse events were the most common reasons for stopping ER niacin/laropiprant during 3.9 years’ follow-up. The analyses presented here identified three major previously unknown hazards of ER niacin. ER niacin/laropiprant increased the risk of statin-related myopathy almost five-fold, and this effect was greater among participants in China than Europe. ER niacin/laropiprant also increased the risk of bleeding (intracranial, gastrointestinal and other sites) and infection. Compared to placebo there was an absolute excess of 3.1% of serious adverse events (excluding cancer and major vascular events [MVEs]) among participants assigned ER niacin/laropiprant. ER niacin/laropiprant did not significantly reduce MVEs. These findings suggest that the use of niacin to reduce vascular risk should now be reconsidered.