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Öğe An analytical ultracentrifugation based study on the conformation of lambda carrageenan in aqueous solution(Elsevier Sci Ltd, 2013) Almutairi, Fahad M.; Adams, Gary G.; Kök, Mehmet Şamil; Lawson, Christopher J.; Gahler, RolandThe conformation and heterogeneity of lambda-carrageenan, a sulphonated galactan from red seaweed, solubilised in aqueous solvent with the assistance of microwave irradiation, has been assessed by a combination of analytical ultracentrifugation, size-exclusion chromatography, light scattering and capillary viscometry. Preparations appeared generally unimodal on the basis of sedimentation coefficient distributions from sedimentation velocity although at the highest concentrations a shoulder appears with a sedimentation coefficient approximately 1.1 times greater than that of the main component. Even under conditions commensurate with charge suppression simple linear regression was insufficient to represent non-ideal concentration dependence and the extraction of the Gralen concentration dependence parameter k(s). A more general fitting algorithm was therefore employed. Mark-Houwink-Kuhn-Sakurada analysis of the change in intrinsic viscosity [eta] with molecular weight, together with the Wales-van Holde ratio (combination of k(s), with [eta]) point to an extended flexible conformation for lambda-carrageenan in the (weight average) molecular weight range M-w = 340,000-870,000 g/mol. The origin of the larger sedimentation coefficient component appearing at the higher concentrations is considered. (C) 2013 Elsevier Ltd. All rights reserved.Öğe Application and use of Inulin as a tool for therapeutic drug delivery(Nottingham Univ Press, 2012) Imran, Shahwar; Gillis, Richard B.; Kök, Mehmet Şamil; Harding, Stephen E.; Adams, Gary G.Inulin is a polysaccharide with an extensive range of therapeutic uses such as a vehicle in drug delivery vehicle, as a diagnostic/analytical tool or as a dietary fibre with additional health benefits. In the main, much research has focussed on inulin as a drug delivery carrier for colon-targeted drug delivery. The justification for this is its potential to survive the stomach's acidic environment. This unique stability and strength is utilized in many ways to deliver drugs safely to colon, where they can be easily absorbed through the gut epithelium into the blood. Inulin based hydrodynamic research will be useful to discover the potential of inulin.Öğe Application of recent advances in hydrodynamic methods for characterising mucins in solution(Springer, 2016) Almutairi, Fahad M.; Hernandez Cifre, Jose-Gines; Adams, Gary G.; Kök, Mehmet Şamil; Mackie, Alan R.Mucins are the primary macromolecular component of mucus-nature's natural lubricant-although they are poorly characterised heterogeneous substances. Recent advances in hydrodynamic methodology now offer the opportunity for gaining a better understanding of their solution properties. In this study a combination of such methods was used to provide increased understanding of a preparation of porcine intestinal mucin (PIM), MUC2 mucin, in terms of both heterogeneity and quantification of conformational flexibility. The new sedimentation equilibrium algorithm SEDFIT-MSTAR is applied to yield a weight average (over the whole distribution) molar mass of 7.1 x 10(6) g mol(-1), in complete agreement with size exclusion chromatography coupled with multi-angle light scattering (SEC-MALS), which yielded a value of 7.2 x 10(6) g mol(-1). Sedimentation velocity profiles show mucin to be very polydisperse, with a broad molar mass distribution obtained using the Extended Fujita algorithm, consistent with the elution profiles from SEC-MALS. On-line differential pressure viscometry coupled to the SEC-MALS was used to obtain the intrinsic viscosity [eta] as a function of molar mass. These data combined with sedimentation coefficient data into the global conformation algorithm HYDFIT show that PIM has a flexible linear structure, with persistence length L (p) similar to 10 nm and mass per unit length, M (L) similar to 2380 g mol(-1) nm(-1), consistent with a Wales-van Holde ratio of similar to 1.2 obtained from the concentration dependence of the sedimentation coefficient.Öğe Characterisation of insulin analogues therapeutically available to patients(Public Library Science, 2018) Adams, Gary G.; Meal, Andrew; Morgan, Paul S.; Alzahrani, Qushmua E.; Zobel, Hanne; Lithgo, Ryan; Kök, Mehmet ŞamilThe structure and function of clinical dosage insulin and its analogues were assessed. This included 'native insulins' (human recombinant, bovine, porcine), 'fast-acting analogues' (aspart, glulisine, lispro) and 'slow-acting analogues' (glargine, detemir, degludec). Analytical ultracentrifugation, both sedimentation velocity and equilibrium experiments, were employed to yield distributions of both molar mass and sedimentation coefficient of all nine insulins. Size exclusion chromatography, coupled to multi-angle light scattering, was also used to explore the function of these analogues. On ultracentrifugation analysis, the insulins under investigation were found to be in numerous conformational states, however the majority of insulins were present in a primarily hexameric conformation. This was true for all native insulins and two fast-acting analogues. However, glargine was present as a dimer, detemir was a multi-hexameric system, degludec was a dodecamer (di-hexamer) and glulisine was present as a dimer-hexamer-dihexamer system. However, size-exclusion chromatography showed that the two hexameric fast-acting analogues (aspart and lispro) dissociated into monomers and dimers due to the lack of zinc in the mobile phase. This comprehensive study is the first time all nine insulins have been characterised in this way, the first time that insulin detemir have been studied using analytical ultracentrifugation and the first time that insulins aspart and glulisine have been studied using sedimentation equilibrium. The structure and function of these clinically administered insulins is of critical importance and this research adds novel data to an otherwise complex functional physiological protein.Öğe Extraction, isolation and characterisation of oil bodies from pumpkin seeds for therapeutic use(Elsevier Sci Ltd, 2012) Adams, Gary G.; Imran, Shahwar; Wang, Sheng; Mohammad, Abubaker; Kök, Mehmet ŞamilPumpkin, a member of the Cucurbitaceae family has been used frequently as functional medicines for therapeutic use. Several phytochemicals such as polysaccharides, phenolic glycosides, 13-hydroxy-9Z, 11E-octadecatrienoic acid from the leaves of pumpkin, proteins from germinated seeds, have been isolated. Here the influence of pH, ionic strength, and temperature on the properties and stability of oil bodies from pumpkin (Cucurbita) were determined with a view to patterning oil body size and structure for future therapeutic intervention. Oil bodies from pumpkin seeds were extracted, isolated, characterised using optical microscopy, zeta potential and particle size distribution obtained. During microscopic analysis, the oil bodies were more intact and in an integrated form at the time of extraction but were ruptured with time. Water extracted oil bodies were spherical for all four layers where cream had larger oil bodies then upper curd. Lower curd and supernatant had considerably smaller size with lower curd densely packed and seemed to be rich in oil bodies than any of the four layers. At pH 3, in the absence of salt, the zeta potential is approximately +30 mV, but as the salt concentration increases, the C potential rises at 10 mM but then decreases over the salt range. This trend continues for the upper curd, lower curd and the supernatant and the degree of the reduction (mV) in zeta potential is of the order cream < upper curd < lower curd < supernatant. At pH 7.4, physiological pH, the changes in salt concentration from 10 to 100 mM reduce the zeta potential significantly across all layers such that increased salt concentrations induce negative potentials. Increasing the salt concentrations still further, however, does not make the C potential more negative. However, at pH 9 the zeta potential falls from 0 to 50 mV as the salt concentration increases with the largest reduction shown with 100 mM salt. Particle size distribution at increasing pH salt concentration shows the average size distribution of pumpkin seed oil bodies at an increasing pH (3, 7.4 and 9) and salt concentration (0, 10,50 and 100 mM) across all four layers. The lowest average size distributions are seen at pH 7.4 across all four layers especially within the cream and upper curd layers. At pH 3 and 9, the highest average size distributions are seen in the lower curd and cream layers. Oil bodies can be extracted, isolated and from pumpkins using an aqueous extraction method and may prove to be a useful new source of lipids for application in patterning therapeutics for clinical use. (C) 2012 Elsevier Ltd. All rights reserved.Öğe Glargine and degludec: solution behaviour of higher dose synthetic insulins(Nature Publishing Group, 2017) Adams, Gary G.; Alzahrani, Qushmua; Jiwani, Shahwar Imran; Meal, Andrew; Morgan, Paul S.; Kök, ŞamilSingle, double and triple doses of the synthetic insulins glargine and degludec currently used in patient therapy are characterised using macromolecular hydrodynamic techniques (dynamic light scattering and analytical ultracentrifugation) in an attempt to provide the basis for improved personalised insulin profiling in patients with diabetes. Using dynamic light scattering and sedimentation velocity in the analytical ultracentrifuge glargine was shown to be primarily dimeric under solvent conditions used in current formulations whereas degludec behaved as a dihexamer with evidence of further association of the hexamers ("multi-hexamerisation"). Further analysis by sedimentation equilibrium showed that degludec exhibited reversible interaction between mono-and-di-hexamer forms. Unlike glargine, degludec showed strong thermodynamic non-ideality, but this was suppressed by the addition of salt. With such large injectable doses of synthetic insulins remaining in the physiological system for extended periods of time, in some case 24-40 hours, double and triple dose insulins may impact adversely on personalised insulin profiling in patients with diabetes.Öğe Hydrodynamic characterisation of chitosan and its interaction with two polyanions: DNA and xanthan(Elsevier Sci Ltd, 2015) Almutairi, Fahad M.; Erten, Tayyibe; Adams, Gary G.; Hayes, Maria; McLoughlin, Padraig; Kök, Mehmet ŞamilChitosan, a soluble polycationic derivative of insoluble chitin, has been widely considered for use in the food, cosmetic and pharmaceutical industries. Commercial ("C") and in-house laboratory ("L") prepared chitosan samples extracted from crustaceous shells with different molecular weight and degrees of acetylation (25% and 15%) were compared with regards to (i) weight-average molecular weight (M-w); (ii) sedimentation coefficient (s(20,w)(o)) distribution, and (iii) intrinsic viscosity ([eta]). These parameters were estimated using a combination of analytical ultracentrifugation (AUC), size exclusion chromatography coupled to multi-angle laser light scattering (SEC-MALS) and differential pressure viscometry. Polydisperse distributions were seen from sedimentation coefficient distributions and elution profiles from SEC-MALS. M-w values obtained for each sample by sedimentation equilibrium measurements were in excellent agreement with those obtained from SEC-MALS. Mark-Houwink-Kuhn-Sakurada (MHKS) and Wales van Holde analyses of the data all suggest a semi-flexible conformation. The principle of co-sedimentation was then used to monitor the interactions of the two different molecular weights of L chitosans with two polyanions, DNA and xanthan (another double helical high molecular weight molecule). Interactions were clearly observed and then quantified from the changes in the sedimentation coefficient distribution of the mixture compared to unmixed controls using sedimentation velocity. The interactions appeared to show a strong dependence on molecular weight. The relevance of this for DNA condensation applications is indicated. (C) 2014 Elsevier Ltd. All rights reserved.Öğe The hypoglycaemic effect of pumpkins as anti-diabetic and functional medicines(Elsevier, 2011) Adams, Gary G.; Imran, Shahwar; Wang, Sheng; Mohammad, Abubaker; Kök, Mehmet ŞamilDiabetes mellitus is considered as a common, growing, serious, costly, and potentially preventable public health problem. In 2030, the number of people with diabetes is estimated to increase from 117 million in 2000 to 366 million. The prevalence of diabetes has and will continue to have burden on the health and finances of economic climates, which in turn, will impact on individuals, families and nations. There are many different types of insulins available to treat diabetes, but there are still physiological consequences for such use. Alternatives are, therefore, required and this includes herbal preparations as well as dietary plants in the form of curcubitaceae (pumpkin). Pumpkin is widely considered to have active hypoglycaemic properties. Pumpkin is a plant, which has been used frequently as functional food or medicine and belongs to the family Cucubitaceae, and consists of succulent stem with numerous seeds. Based on previous evidence of its fruit pulp, it is reported to have anti-diabetic effects. This review has focused on the main medicinal properties of pumpkin and how this has been used in animal models, and point out areas for future research to further elucidate mechanisms whereby this compound may reduce disease risk. (C) 2011 Elsevier Ltd. All rights reserved.Öğe The Hypoglycemic effect of pumpkin seeds, trigonelline (TRG), nicotinic acid (NA), and D-Chiro-inositol (DCI) in controlling glycemic levels in diabetes mellitus(Taylor & Francis Inc, 2014) Adams, Gary G.; Imran, Shahwar; Wang, Sheng; Mohammad, Abubaker; Kök, Muhammet ŞamilIn the contemporary society, diabetes mellitus is considered as a common, growing, serious, costly, and potentially preventable public health problem. It is forecasted that in 2030, the number of people with diabetes will go up from 117 million in 2000 to 366 million in 2030. The prevalence of diabetes will place a huge burden on health and financial structures of countries, and these will impact on individuals, as well as families and nations. Polysaccharides, para-aminobenzoic acid, fixed oils, sterol, proteins, and peptides are biologically active ingredients, which are found in pumpkins. The chemicals within pumpkins such as the fruit pulp, oil from ungerminated seeds, and protein from germinated seeds have hypoglycemic properties. Preliminary investigation showed that pumpkin seeds, and the macromolecules, therein, such as Trigonelline (TRG), Nicotinic acid (NA), and dchiro-inositol (DCI), possess hypoglycemic properties and could assist in maintaining glycemic control.Öğe The interaction of dietary fibres with disulphide bonds (S-S) and a potential strategy to reduce the toxicity of the gluten proteins in coeliac disease(2012) Adams, Gary G.; Kök, M. Şamil; Imran, Shahwar; Harding, Stephen E.; İlyas, Mohammad; Tatham, Arthur S.With a prevalence of 1% in western populations, coeliac disease (CD) is one of the better understood human leukocyte antigen system (HLA) linked disorders (Green and Cellier 2007). Despite the fact that CD shares immunological features with inflammatory bowel disease, it is characterized by: (1) a defined trigger (prolamins from wheat, barley and rye and in some individuals, oats); (2) the presence of HLA class II genes, HLA-DQ2 or HLA-DQ8, and (3) the generation of circulating auto antibodies to the enzyme tissue transglutaminase (TG2). TG2 catalyses the formation of a covalent bond between protein free amino groups and the g-carboxamide groups of glutamine residues, which constitute some 30-40 mol%, of the prolamins, this increases their affinity to HLA-DQ2 or HLA-DQ8 proteins (Schuppan 2000). As a result, CD4 T-helper 1 T-cell activation occurs, which can result in intestinal mucosal inflammation, malabsorption, and numerous secondary complications. When conducting severity assessments of coeliac disease, duodenal histology showing intraepithelial lymphocytosis, crypt hyperplasia, and various degrees of villous atrophy, in conjunction with clinical observations, are considered to be the gold standard for diagnosis.Öğe Molecular weight distribution analysis by ultracentrifugation : adaptation of a new approach for mucins(Elsevier Sci Ltd, 2013) Gillis, Richard B.; Adams, Gary G.; Wolf, Bettina; Berry, Monica; Besong, Tabot M. D.; Kök, Şamil MehmetMucins are the key macromolecular component of mucus, nature's natural lubricant, and one of the most important physical properties is their molecular weight distribution. A new approach for polydisperse polymers was recently published based on sedimentation velocity in the analytical ultracentrifuge and converts a distribution of sedimentation coefficient g(s) vs. s plot into a distribution of molecular weight utilising the power-law or scaling relationship between the sedimentation coefficient and molecular weight, s = kappa(s) M-w(b) where s is the sedimentation coefficient, M-w, is the weight average molecular weight and kappa(s) and bare characteristic coefficients related to conformation. We investigate the possibility of using a large database of previously published values of s an M to define kappa(s) and b for both aqueous solution and aqueous solution supplemented by 6 M guanidine hydrochloride (a solvent which helps to minimise sample degradation). These values are then applied to a study of the molecular weight distributions of preparations of human gastric mucin in the different solvents and at different stages of purification. (C) 2012 Elsevier Ltd. All rights reserved.Öğe Polysaccharide drug delivery systems based on pectin and chitosan(Nottingham Univ Press, 2010) Morris, Gordon A.; Kök, Mehmet Şamil; Harding, Stephen E.; Adams, Gary G.Chitosans and pectins are natural polysaccharides which show great potential in drug delivery systems. Chitosans are a family of strongly polycationic derivatives of poly-N-acetyl-Dglucosamine. This positive charge is very important in chitosan drug delivery systems as it plays a very important role in mucoadhesion (adhesion to the mucosal surface). Other chitosan based drug delivery systems involve complexation with ligands to form chitosan nanoparticles with can be used to encapsulate active compounds. Pectins are made of several structural elements the most important of which are the homogalacturonan (HG) and type I rhamnogalacturonan (RG-I) regions often described in simplified terms as the "smooth" and "hairy" regions respectively. Pectin HG regions consist of poly-glacturonic acid residues which can be partially methyl esterified. Pectins with a degree of methyl esterification (DM) > 50% are known as high methoxyl (HM) pectins and consequently low methoxyl (LM) pectins have a DM < 50%. Low methoxyl pectins are of particular interest in drug delivery as they can form gels with calcium ion (Ca2+) which has potential applications especially in nasal formulations. In this chapter we will discuss the physicochemical properties of both chitosans and pectins and how these translate to current and potential drug delivery systems.Öğe Ultracentrifuge methods for the analysis of polysaccharides, glycoconjugates, and lignins(Elsevier Academic Press Inc, 2015) Harding, Stephen E.; Adams, Gary G.; Almutairi, Fahad; Alzahrani, Qushmua; Erten, Tayyibe; Kök, Mehmet ŞamilAlthough like proteins, polysaccharides are synthesized by enzymes, unlike proteins there is no template. This means that they are polydisperse, do not generally have compact folded structures, and are often very large with greater nonideality behavior in solution. This chapter considers the relevant analytical ultracentrifuge methodology available for characterizing these and related carbohydrate-based systems and information this methodology supplies, in terms of sizes, shapes, and interactions using a comprehensive range of examples, including glycoconjugates and lignins. The relevance and potential of recent software developments such as SEDFIT-MSTAR, the Extended Fujita algorithm, and HYDFIT are considered.
