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京都大学 / 新制・課程博士 / 博士(医学) / 甲第23751号 / 医博第4797号 / 新制||医||1055(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 寺田 智祐, 教授 江藤 浩之, 教授 髙折 晃史 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

There are many reports indicating the presence of various emerging contaminants (ECs) in treated wastewater and other water sources. The detection of such contaminants in the environment and the ability of these contaminants to pose potential threats to the environment at very low concentrations have led to a need for more efficient treatment technologies. Cyclodextrins (CDs) have gained significant interest as an alternative adsorbent for water and wastewater treatment because of their unique physico-chemical characteristics and excellent selectivity towards organic compounds. The property of CD to form inclusion complexes with various molecules through host-guest interactions has made it a useful compound for the removal of a number of contaminants from water and wastewater. The overall goal of the study is to identify and develop a novel adsorbent for the removal of ECs of interest. The specific objectives are a) to synthesize various beta-cyclodextrin (BCD) based adsorbents by coating BCD onto different supports such as silica, filter paper, iron oxide, and zeolite, b) to perform batch and column experiments using the developed adsorbents, c) to evaluate the performance of the adsorbents in different water matrices such as MQ water, simulated wastewater in presence of humic acid, and real municipal wastewater, d) to study the regeneration potential of the adsorbents. In this research, various (BCD) based hybrid adsorbents were synthesized and their performances were evaluated based on the removal of selected ECs. At first, chemically bonded BCD onto silica particles as hybrid adsorbents were synthesized by using crosslinking agents and copolymers. Three different methods were used to synthesize 14 different BCD coated silica adsorbents. The adsorbent prepared by reacting BCD with hexamethylene diisocyanate (HMDI) as crosslinking agent and dimethyl sulfoxide (DMSO) as solvent showed best results in removing the ECs studied. The adsorbent showed more than 95% removal of 17β-estradiol (in single component) and more than 90% of most of the estrogens (mixture of 12), more than 99% of perfluorooctanoic acid (PFOA) (in single component) and more than 90% of most of the PFCs (mixture of 10), and a maximum of 90% removal in case of BPA. The adsorption capacity of the developed adsorbent was observed to be higher for the removal of 17β-estradiol and PFOA than that of commercially available activated carbon (F400) in MQ water. In order to represent the real environmental scenario, further batch experiments were conducted for the removal of two PFCs (PFOA and PFOS (perfluorooctane sulfonic acid)), 17β-estradiol, and BPA at environmentally relevant concentrations from wastewater. The adsorbent was effective in removing the ECs that were spiked in the secondary effluent of a municipal wastewater treatment plant. Furthermore, the adsorbent was successfully regenerated with methanol over four cycles without significant loss in its adsorption capacity for the removal of PFOA and estrogens. Ozonation as an alternative method of regeneration was also used and the process was also very effective in regenerating the adsorbent over seven successive cycles for the removal of BPA and 17β-estradiol. The characterization of the adsorbents using FTIR, TGA, and TEM confirmed the coating of BCD onto silica particles. The TGA results showed high thermal stability of the adsorbent (upto 300oC). As an alternative to chemical impregnation, another method of synthesis was developed where various BCD based hybrid adsorbents were synthesized by physically impregnating hydroxypropyl BCD (hpBCD) polymer onto three different supports: iron oxides, zeolite, and filter paper. The hpBCD impregnated filter papers were synthesized by solvent evaporation method and different adsorbents were synthesized by varying the polymer loadings. The polymer loading was optimized based on the performance of the modified (polymer impregnated) filter paper in terms of its filtration capacity as well as adsorption capacity to remove PFOA and BPA. The magnetic adsorbent was prepared by mixing hpBCD polymer with iron oxide (Fe3O4) particles. It was observed that by increasing the mixing time of the support (Fe3O4) with the polymer from 48 to 96 hr, the adsorption capacity of the adsorbent (hpBCD polymer coated Fe3O4) could be significantly enhanced. The same approach was also used to synthesize hpBCD polymer coated zeolite adsorbent and both adsorbents (hpBCD/zeolite and hpBCD/Fe3O4) were effective in removing the selected ECs from MQ water, simulated water, and wastewater. / Civil Engineering

As a response of the need for a natural antimicrobial to replace sodium benzoate's use as a preservative in beverages, twenty eight compounds known to have antimicrobial activity were evaluated to quantify their solubility. Twenty three of the compounds evaluated are components of plant essential oils and the remaining five compounds are alkyl esters of para-hydroxybenzoic acid. The test compounds were evaluated for aqueous solubility as well as their solubility in an acid-based beverage mixture. The compounds were found to be practically insoluble (< 100 mg/L), very slightly soluble (100 mg/L – 1,000 mg/L) or slightly soluble (1,000 mg/L to 10,000 mg/L). o-Methoxycinnamaldehyde, trans,trans-2,4-decadienal, cinnamic acid, and citronellol were complexed with α- and β-cyclodextrin and evaluated through phase solubility analyses. The complexes formed showed improved aqueous solubility for all compounds. Complexation with α-CD resulted in an increase of aqueous solubility of o-methoxycinnamaldehyde by 10-fold, trans,trans-2,4-decadienal by 3.2-fold, cinnamic acid by 6.3-fold, and citronellol by 8-fold. In addition, complexation with β-CD resulted in an increase of aqueous solubility of o-methoxycinnamaldehyde by 1.6-fold, trans,trans-2,4-decadienal by 3.1-fold, cinnamic acid by 1.7-fold, and citronellol by 1.6- fold. The storage stability of the α-CD complexes of o-methoxycinnamaldehyde trans,trans-2,4-decadienal and citronellol were evaluated for 7 days in an acid-based beverage solution by SPME GC-MS. The complexes exhibited varying levels of degradation throughout the duration of the study all. The concentration of o-methoxycinnamaldehyde detected by SPME GC-MS decreased by 61.7%. Similarly, the concentration of trans,trans-2,4-decadienal and that of citronellol decreased by 62.7% and 43% respectively. Additionally, a comparison by UV/Vis of the storage stability of the complexes stored in glass and PET containers was performed. The storage stability comparison proved that absorption into the PET polymer membrane did not occur. / Master of Science

In response to a need for a natural antimicrobial to replace sodium benzoate, cinnamic acid was chosen. Due to cinnamic acid's solubility issues, α-cyclodextrin was used as a host molecule to form an inclusion complex with the cinnamic acid molecule. The cinnamic acid: α-cyclodextrin inclusion complex was then characterized using phase solubility analysis, proton nuclear magnetic resonance (H-NMR), and solid inclusion. Phase solubility analysis verified the maximum amount of cinnamic acid that α-cyclodextrin was able to host. H-NMR was used to determine the complex association constant, determine the chemical shifts of available protons, and yield a stoichiometry for the complex. The solid inclusion complex allowed for a physical formation of the complex, yielding further information in support of the complex stoichiometry. Microbiological tests were also performed to quantify the antimicrobial abilities of the complex, the guest, and the host against the yeast Saccharomyces cerevisiae and mold Paecilomyces variotii. Results indicated that approximately 990.29 ppm in aqueous solution was the maximum amount of cinnamic acid in the complex. The 2:1 stoichiometry yields an association constant of 21.7 M-1. Results also indicated that the cinnamic acid readily conformed to fit within the α-cyclodextrin host molecule, which remained a rigid structure. An 8.9% weight to weight of cinnamic acid was calculated for the solid inclusion again reinforcing a 2:1 stoichiometry. Microbiological studies showed little to no inhibition power by the complex at varying concentrations against S. cerevisiae and P. variotii. Free cinnamic acid showed greater antimicrobial activity compared with free α-cyclodextrin and the complex. / Master of Science in Life Sciences

Microcosms were constructed from aquifer sediment samples taken from an actively degrading chlorinated solvent contaminated site located in Virginia Beach, Virginia. The objective of this study was to determine if and how the addition of cyclodextrin (CD) affects reductive dechlorination of chlorinated ethenes. After chlorinated solvent degradation rates were established in anaerobic and aerobic microcosms, 100 mg/L of CD solution was added for a period of 21 days. CD was then removed after 26 days to simulate the degradation response of the aquifer in a post CD injection environment. Degradation rates were determined by analyzing PCE, TCE, and cis-DCE concentration data over the various phases of the experiment. Results from this study indicated that chlorinated solvent degradation could be either impaired or facilitated by the addition of CD. CD appeared to stimulate one anaerobic microcosm (IY-2c) where daughter production had not previously occurred. The activity of this microcosm was greatly enhanced by the addition of CD (0 uM/day to 13.89 uM/day). However, biotransformation of PCE in another anaerobic microcosm in which reductive dechlorination was occurring, ceased after the addition of CD (IY-1a). In a third group of microcosms the rate and extent of reductive dechlorination was greatly enhanced by the addition of CD. The effect of adding CD was also found to be highly dependent on the redox conditions in the microcosm, specifically if the conditions were strongly reducing. The most active microcosms, found in the Aerobic Group, also had the lowest ferrous iron concentrations (3.57 mg/L for BY-1a, 2.25 mg/L for BY-1b, and 0.41 mg/L for BY-1c). The microcosm (IY-2b) that showed no daughter production had the highest level of ferrous iron (44.22 mg/L). This study presents a qualitative approach to the affect of CD on MNA. / Master of Science

Tesis por compendio / [EN] Cryopreserved boar sperm is not used extensively for artificial insemination due to poor fertility rates of the sperm after freezing and thawing. The sperm membrane is damaged when cooled from body temperature to 5 ºC (cold shock), as well as during the freeze-thaw process. Increasing the cholesterol content of boar sperm membranes could increase their post-thaw survival, similarly to other species that are cold shock sensitive. Cholesterol can be easily added to sperm membranes using cholesterol-loaded cyclodextrins (CLC). Treating sperm from different species susceptible to cold-shock with CLC before cryopreservation improves sperm cryosurvival. Egg yolk and glycerol are common constituents of extenders used for boar sperm cryopreservation. However, conventional freezing extenders could not be the appropriate for CLC-treated sperm. The aim of this Thesis is to evaluate cryosurvival of CLC or cyclodextrin-treated boar sperm in three different conditions: using conventional freezing extenders, using extenders with alternative concentrations of glycerol and egg yolk and using amides as cryoprotectants. CLC or methyl- ß-cyclodextrin treatment (1 mg/120 x 106 sperm) prior to cryopreservation using a conventional freezing extenders provided either slight or no benefit, respectively, to post-thaw sperm plasma membrane integrity (+ 8%; P < 0.05) and motility (P > 0.05). In addition, sperm from both, good and poor freezers, responded similarly to CLC treatment (P > 0.05). Reduction in egg yolk concentration from 20 to 10% was detrimental for post-thaw sperm viability, even in semen treated with CLC (- 12%; P < 0.05). On the other hand, it was observed that traditional concentration of glycerol (3%) was not the appropriate to freeze CLC-treated sperm (- 13% viable sperm compared to control; P < 0.05). Thus, CLC-treated sperm showed a higher tolerance (+ 13 % sperm viability; P < 0.05) to high glycerol concentrations (5%) than non-treated sperm. Regarding the efficacy of amides as cryoprotectants, three of the amides (lactamide, acetamide and formamide) produced deleterious effects in fresh boar sperm (P < 0.05). The other amides (methylformamide, dimethylacetamide and dimethylformamide) efficiently improved post-thaw sperm viability (+ 5 to 15 %; P < 0.05) but negatively affected the sperm motility (- 11 to 16% total motile sperm; P < 0.05) and the sperm fertilizing ability in vitro (dimethylformamide: - 64 % penetration rate; P < 0.05), irrespective of the sperm treatment. On the other hand, CLC-treated samples showed better in vitro fertilizing ability than control samples when glycerol was used as cryoprotectant (+ 2 penetrated spermatozoa/oocyte; P < 0.05). The results obtained in this Thesis suggest that conventional freezing protocols should be optimized for CLC-treated boar sperm in order to obtain the benefit of CLC treatment observed in other species sensitive to cold shock. / [ES] Las inseminaciones artificiales en la especie porcina se realizan habitualmente con semen refrigerado, debido a las bajas tasas de fertilidad obtenidas con el semen congelado-descongelado. La membrana del espermatozoide sufre importantes daños cuando es sometida a la fase de enfriamiento desde la temperatura corporal hasta alcanzar los 5 ºC (choque térmico), así como durante el proceso de congelación y descongelación. El aumento del contenido de colesterol en las membranas de los espermatozoides de cerdo podría mejorar su supervivencia tras la descongelación, como sucede en otras especies sensibles al choque térmico. Este incremento en la cantidad de colesterol se puede realizar fácilmente utilizando ciclodextrinas saturadas de colesterol (CLC). El tratamiento con CLC de espermatozoides de varias especies susceptibles al choque térmico antes de la congelación ha conseguido mejorar su supervivencia tras la descongelación. En los protocolos convencionales de congelación de semen porcino se utilizan habitualmente diluyentes de congelación compuestos por yema de huevo y glicerol, sin embargo, puede que estos diluyentes de congelación convencionales no sean los más apropiados para congelar espermatozoides tratados con CLC. El objetivo de esta Tesis es evaluar la supervivencia a la congelación de los espermatozoides porcinos tratados con CLC o ciclodextrinas utilizando diluyentes de congelación convencionales, utilizando concentraciones alternativas tanto de yema de huevo como de glicerol o utilizando amidas en lugar de glicerol como crioprotectores Utilizando diluyentes convencionales, el tratamiento con 1mg de CLC o de metil-ß-ciclodextrina/120 millones de espermatozoides previamente a la congelación proporcionó una leve mejora de la integridad de la membrana plasmática espermática (+ 8%; P < 0,05) y ningún beneficio sobre la movilidad espermática (P > 0,05). Además, la respuesta al tratamiento con CLC fue similar independientemente de si los espermatozoides procedían de verracos buenos o malos congeladores (P > 0,05). Una reducción de la concentración de yema de huevo de un 20 a un 10% fue perjudicial para la supervivencia de los espermatozoides tras la descongelación, incluidos aquellos que habían sido tratados previamente con CLC (- 12% espermatozoides vivos; P < 0,05). Por otro lado, observamos que las concentraciones de glicerol utilizadas habitualmente (3%) no son las más apropiadas para congelar espermatozoides tratados con CLC (- 13 % viabilidad espermática comparando con las muestras control; P < 0,05), ya que éstos mostraron una mayor tolerancia (+ 13 % espermatozoides vivos; P < 0,05) que las muestras control a las concentraciones de glicerol más altas (5%). Con respecto a la eficacia de las amidas como crioprotectores para semen porcino, tres de las amidas (lactamida, acetamida y formamida) produjeron efectos perjudiciales durante su incubación con semen fresco (P < 0,05). El resto de amidas evaluadas (metilformamida, dimetilacetamida y dimetilformamida) mejoraron eficientemente la viabilidad espermática tras la congelación (+ 5 a 15 %; P < 0,05), sin embargo, afectaron negativamente tanto la movilidad espermática (- 11 a 16% móviles totales; P < 0,05) como la capacidad de fecundación in vitro (dimetilformamida: - 64 % en la tasa de penetración; P < 0,05), independientemente de si el semen fue tratado con CLC o no. Por otro lado, las muestras tratadas con CLC mostraron mejor capacidad de fecundación in vitro que las muestras control cuando se utilizó el glicerol como crioprotector (+ 2 espermatozoides penetrados/ovocito; P < 0,05). Los resultados obtenidos en esta Tesis sugieren que sería necesaria la adecuación de los protocolos de congelación convencionales para congelar semen porcino tratado con CLC con el propósito de alcanzar los claros beneficios obtenidos con dicho tratamiento cuando ha sido evaluado en otras especies sensibles al choque térmico. / [CA] Les inseminacions artificials en l'espècie porcina es realitzen habitualment amb semen refrigerat, a causa de les baixes taxes de fertilitat obtingudes amb el semen congelat-descongelat. La membrana de l'espermatozoide pateix importants danys quan és sotmesa a la fase de refredament des de la temperatura corporal fins a arribar als 5 ºC (xoc tèrmic), així com durant el procés de congelació i descongelació. L'augment del contingut de colesterol a les membranes dels espermatozoides de porc podria millorar la seva supervivència després de la descongelació, com succeeix en altres espècies sensibles al xoc tèrmic. Aquest increment en la quantitat de colesterol es pot realitzar fàcilment utilitzant ciclodextrines saturades de colesterol (CLC). El tractament amb CLC d'espermatozoides de diverses espècies susceptibles al xoc tèrmic abans de la congelació ha aconseguit millorar la seva supervivència després de la descongelació. En els protocols convencionals de congelació de semen porcí s'utilitzen habitualment diluents de congelació compostos per rovell d'ou i glicerol, però, pot ser que aquests diluents de congelació convencionals no siguin els més apropiats per congelar espermatozoides tractats amb CLC. L'objectiu d'aquesta Tesi és avaluar la supervivència a la congelació dels espermatozoides porcins tractats amb CLC o ciclodextrines utilitzant diluents de congelació convencionals, utilitzant concentracions alternatives tant de rovell d'ou com de glicerol o utilitzant amides en lloc de glicerol com crioprotectors Utilitzant diluents convencionals, el tractament amb 1 mg de CLC o de metil-ß-ciclodextrina / 120 milions d'espermatozoides prèviament a la congelació va proporcionar una lleu millora de la integritat de la membrana plasmàtica espermàtica (+ 8%; P <0,05) i cap benefici sobre la mobilitat espermàtica (P> 0,05). A més, la resposta al tractament amb CLC va ser similar independentment de si els espermatozoides procedien de verros bons o dolents congeladors (P> 0,05). Una reducció de la concentració de rovell d'ou d'un 20 a un 10% va ser perjudicial per a la supervivència dels espermatozoides després de la descongelació, inclosos aquells que havien estat tractats prèviament amb CLC (- el 12% espermatozoides vius; P <0,05) . D'altra banda, observem que les concentracions de glicerol utilitzades habitualment (3%) no són les més apropiades per congelar espermatozoides tractats amb CLC (- 13% viabilitat espermàtica comparant amb les mostres control; P <0,05), ja que aquests van mostrar una major tolerància (+ 13% espermatozoides vius; P <0,05) que les mostres control a les concentracions de glicerol més altes (5%). Pel que fa a l'eficàcia de les amides com crioprotectors per semen porcí, tres de les amides (lactamida, acetamida i formamida) van produir efectes perjudicials durant la seva incubació amb semen fresc (P <0,05). La resta de amides avaluades (metilformamida, dimetilacetamida i dimetilformamida) van millorar eficientment la viabilitat espermàtica després de la congelació (+ 5 a 15%, P <0,05), però, van afectar negativament tant la mobilitat espermàtica (- 11 a 16% mòbils totals; P <0,05) com la capacitat de fecundació in vitro (dimetilformamida: - el 64% en la taxa de penetració; P <0,05), independentment de si el semen va ser tractat amb CLC o no. D'altra banda, les mostres tractades amb CLC van mostrar millor capacitat de fecundació in vitro que les mostres control quan es va utilitzar el glicerol com crioprotector (+ 2 espermatozous penetrats / oòcit; P <0,05). Els resultats obtinguts en aquesta Tesi suggereixen que seria necessària l'adequació dels protocols de congelació convencionals per congelar semen porcí tractat amb CLC amb el propòsit d'assolir els clars beneficis obtinguts amb el tractament quan ha estat avaluat en altres espècies sensibles al xoc tèrmic. / Blanch Torres, E. (2015). Treating boar sperm with cholesterol-loaded cyclodextrins or cyclodextrins prior to cryopreservation: effects on post-thaw in vitro sperm quality of sperm cryopreserved in different freezing extenders [Tesis doctoral]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/58773 / Compendio

Yes / There is a need to understand the nature of aggregation of cyclodextrins (CDs) with guest molecules in increasingly complex formulation systems. To this end an innovative application of Taylor dispersion analysis (TDA) and comparison with dynamic light scattering (DLS) have been carried out to probe the nature of ICT01-2588 (ICT-2588), a novel tumor-targeted vascular disrupting agent, in solvents including a potential buffered formulation containing 10% hydroxypropyl-β-cyclodextrin. The two hydrodynamic sizing techniques give measurement responses are that fundamentally different for aggregated solutions containing the target molecule, and the benefits of using TDA in conjunction with DLS are that systems are characterised through measurement of both mass- and z-average hydrodynamic radii. Whereas DLS measurements primarily resolve the large aggregates of ICT01-2588 in its formulation medium, methodology for TDA is described to determine the size and notably to quantify the proportion of monomers in the presence of large aggregates, and at the same time measure the formulation viscosity. Interestingly TDA and DLS have also distinguished between aggregate profiles formed using HP-β-CD samples from different suppliers. The approach is expected to be widely applicable to this important class of drug formulations where drug solubility is enhanced by cyclodextrin and other excipients.