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Influence of cholesterol concentration on permeability and microstructure of model skin barrier lipid membranes
Červená, Martina ; Vávrová, Kateřina (advisor) ; Zbytovská, Jarmila (referee)
Cholesterol is a substance of a steroidal nature that has a number of functions in the human body. One of them is also an irreplaceable role in the proper functioning of the skin barrier. Cholesterol is an integral part of the lipid matrix, together with ceramides and free fatty acids in an equimolar ratio (1: 1: 1), and 5% cholesterol sulfate, which fills the intercellular space between stratum corneum cells and is responsible for the barrier properties of the skin. Cholesterol is therefore necessary for epidermal homeostasis, but its role in SC permeability is unknown. The aim of this work was to study the influence of cholesterol concentration on the permeability and microstructure of model lipid membranes of the skin barrier. Eight sets of model membranes with decreasing cholesterol concentrations (100%, 80%, 70%, 60%, 40%, 20%, 0%) and cholesterol alone were studied for which permeability and microstructure were monitored.The study of permeability of membranes was carried out in the Franz diffusion cells by measuring four permeation parameters: water loss, electrical impedance measurement, and the cumulative amount of two model drugs (theophylline and indomethacin). The microstructure of these model membranes was verified by X-ray powder diffraction. X-ray powder diffraction measurements...
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Significant adults in the evolution and development of adolescent
Vávrová, Kateřina ; Gillernová, Ilona (advisor) ; Mertin, Václav (referee)
This bachelor's thesis occupies itself with relationship between significant adults and development of adolescents. Theoretical part describes basic characteristic of these relationships, social development of adolescent, fundamental concepts and selected outcomes of relationship. In the second part is presented my research project. This project is focused on basic characteristics of these relationships in Czech republic and possible connections between these relationships and academical self-efficacy.
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Preparation of Pyrazinamide Derivatives as Potential Antiinfectives. (Study of Structure Activity Relationships)
Juhás, Martin ; Zitko, Jan (advisor) ; Vávrová, Kateřina (referee) ; Svobodová, Radka (referee)
Charles University, Faculty of Pharmacy in Hradec Králové Training Workplace Department of Pharmaceutical Chemistry and Pharmaceutical Analysis Doctoral Degree Program Pharmaceutical Chemistry Candidate PharmDr. Martin Juhás Supervisor doc. PharmDr. Jan Zitko, Ph.D. Advisor prof. PharmDr. Martin Doležal, Ph.D. Title of Doctoral Thesis Preparation of Pyrazinamide Derivatives as Potential Antiinfectives. (Study of Structure Activity Relationships) Antimicrobial resistance is considered one of the greatest threats of the 21st century. Until the COVID-19 pandemic, tuberculosis (TB) was the deadliest infectious disease, responsible for approx. one and a half million deaths each year. Resistance is very common in TB. Therefore, this work deals with the research of new potential antimicrobial substances with a particular focus on the activity against Mycobacterium tuberculosis, the main cause of TB. The introduction of this work briefly describes the current state of research on derivatives of pyrazinamide, which served as the prototype structure of the prepared substances and follows with a basic overview of modern computer-based methods used in drug design. The next part comments on the used chemical and biological methods, and the obtained structure-activity relationships in the presented publications....
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Synthesis of fluorinated serine derivatives and study of their effect on skin barrier function
Župina, Richard ; Vávrová, Kateřina (advisor) ; Opálka, Lukáš (referee)
Charles University, Faculty of Pharmacy in Hradec Králové Department of Organic and Bioorganic Chemistry Supervisor: Prof. PharmDr. Kateřina Vávrová, Ph.D. Consultant: Dr. Georgios Paraskevopoulos, Ph.D. Author: Richard Župina Title of the thesis: Synthesis of fluorinated serine derivatives and study of their effect on skin barrier function The human skin serves as a barrier against physical, chemical and microbial injury. When the skin barrier is perturbed, there is a possibility of microbial infiltration and biochemical damage. Ceramides, as essential components of the skin lipid layer, help to maintain the barrier integrity. Decreased content of skin ceramides in epidermis is connected with skin diseases such as atopic dermatitis and psoriasis. Previous findings of our research group proved that a ceramide analogue with similar steric and hydrophobic parameters to skin ceramides could selectively supplement the recovery of perturbed human skin barrier. The goal of this study was to design a convenient synthesis of ceramide analogues derived from L-serine with two long aliphatic chains. The first chain is amidically bound lignoceric acid and the second chain is either a 10 or a 14 carbon polyfluorinated chain conjugated with the rest of the molecule by an ester bond. Furthermore, the aim of this...
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Preparation and Evaluation of New Ligands Targeting Organic Cation Transporters in the Central Nervous System for the Treatment of Depression
Monteiro, Andrea ; Roh, Jaroslav (advisor) ; Vávrová, Kateřina (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Organic and Bioorganic Chemistry Student: Andrea Monteiro Supervisor: Assoc. Prof. PharmDr. Jaroslav Roh, Ph.D. Specialized supervisors: Nicolas Pietrancosta, Ph.D. Sophie Gautron, Ph.D. Title: Preparation and Evaluation of New Ligands Targeting Organic Cation Transporters in the Central Nervous System for the Treatment of Depression Brain organic cation transporters (OCT2, OCT3) are polyspecific facilitated diffusion transporters that regulate aminergic tonus and have a complementary role to high-affinity monoamine transporters (serotonine transporter SERT, noradrenaline transporter NET and dopamine transporter DAT) in monoamine clearance in the brain. Their complementary characteristics compared to the high-affinity transporters (widespread distribution, broader pharmacological profile) and their involvement in mood-related functions make brain OCT relevant and original targets for the development of novel antidepressants. H2-cyanome is a newly developed prodrug of cyanome that targets OCT. This prodrug showed promising antidepressant efficacy in a rodent model of chronic depression. Despite the positive impact of this prodrug on antidepressant efficacy, its limitation is its high affinity for 1 adrenergic receptors that may...
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Study of barrier lipids in the skin and skin models
Sochorová, Michaela ; Vávrová, Kateřina (advisor) ; Zimčík, Petr (referee) ; Salavec, Miloslav (referee)
1 Abstract Charles University, Faculty of Pharmacy in Hradec Králové Department of Organic and Bioorganic Chemistry Candidate: Mgr. Michaela Sochorová Supervisor: prof. PharmDr. Kateřina Vávrová, Ph.D. Title of doctoral thesis: Study of barrier lipids in the skin and skin models The barrier lipids are found in the intercellular spaces of the uppermost layer of epidermis - stratum corneum (SC). These lipids comprise an approximately equimolar mixture of ceramides (Cer), fatty acids (FA) and cholesterol (Chol). The composition and organization of the lipid mixture is unique and provides a barrier, which protects organism against harmful effects from the surroundings and, at the same time, it protects body from excessive water loss and contributes to homeostasis maintenance. Skin barrier disruption, including altered barrier lipid composition and organization, was described in many skin diseases, for example atopic dermatitis, psoriasis or skin cancer. Study and therapy of these diseases are limited by their complex pathophysiology and a lack of biological material (human skin). Therefore, skin models are appropriate and useful tools for study of skin diseases. The skin models differ in their simplicity/complexity and their preparation therefore they can provide different information. Model lipid membranes are...
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Synthesis and study of 1-O-acylceramides
Jon, Vojtěch ; Vávrová, Kateřina (advisor) ; Opálka, Lukáš (referee)
The extracellular matrix of the uppermost layer of the skin, the stratum corneum (SC), consists of ceramides (Cer), cholesterol (Chol), free fatty acids (FFA) and cholesteryl sulfate (CholS). Cer play an important role in the correct barrier function of mammalian epidermis. A new type of sphingolipids, i.e., 1-O-acyl-Cer, have been found in human SC very recently; however, their role in the SC is unknown. These Cer species contain sphingosine (S) that is N- acylated with non-hydroxylated or α- hydroxylated fatty acid, and moreover, hydroxyl group at C1 in sphingosine is esterified by an additional fatty acid (lignoceric acid, C24 or palmitic acid, C16). Because 1-O-acyl-Cer are not commercially available, we aimed to synthesize physiological 1-O-acyl Cer, i.e., Cer-24NS16, Cer-16NS16 and Cer-24AS16. Moreover, we aimed to study their behaviour on permeability and microstructure of model skin lipid membranes. The 1-O-acyl-Cer were synthesized by an acylation of Cer-NS16 or Cer-AS16 with palmitic or lignoceric acid using N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide and 4- dimethylaminopyridine. Cer-AS16 was prepared by α-bromination of palmitic acid, substitution of bromine by hydroxyl and N-acylation of sphingosine by the prepared acid in the presence N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide...
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Study of azaphthalocyanines as fluorescence quenchers in oligodeoxynucleotide probes
Demuth, Jiří ; Nováková, Veronika (advisor) ; Hocek, Michal (referee) ; Vávrová, Kateřina (referee)
Charles University, Faculty of Pharmacy in Hradec Kralove Department: Department of Pharmaceutical Chemistry and Pharmaceutical Analysis Author: Mgr. Jiří Demuth Supervisor: doc. PharmDr. Veronika Nováková, Ph.D. Consultant: prof. PharmDr. Petr Zimčík, Ph.D. Doctoral Thesis: Study of azaphthalocyanines suitable for quenching of fluorescence in oligodeoxynucleotide probes Phthalocyanines (Pcs) and azaphthalocyanines (AzaPcs) are planar macrocyclic compounds. These synthetic compounds are derived from naturally occurring dyes - porphyrins. Pcs and AzaPcs have very interesting photophysical properties due to their extensive 18 -electron conjugated system. They are used in electrotechnics, material industry or in medicinal applications. Octaalkylamino substituted tetrapyrazinoporphyrazines (TPyzPzs), which belong to AzaPc family, can quench fluorescence of other molecules due to the ultrafast intramolecular charge transfer. This thesis studies this quenching ability of TPyzPzs with the aim to develop efficient fluorescence probes. Such probes could find application in a variety of experiments across scientific disciplines i.e. - biochemistry, forensic or genetic analysis. Synthetic part of dissertation thesis is a continuation of previous investigation of TPyzPzs in our research group. It describes...
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Synthesis and study of ceramides with deuterated acyl chain
Hudská, Klára ; Vávrová, Kateřina (advisor) ; Nováková, Veronika (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Inorganic and Organic Chemistry Candidate: Klára Hudská Supervisor: Doc. PharmDr. Kateřina Vávrová, Ph.D. Title of Diploma Thesis: Synthesis and study of ceramides with deuterated acyl chain Ceramides are a complex group of lipids belonging to sphingolipids. They are the most important component in stratum corneum and play an essential role in protecting the skin from excessive water loss and other environmental damages. Despite the fact that ceramides are a subject of intensive research, the exact effect of their structure on barrier skin function has not been fully explained. The aim of this diploma thesis was to synthesize a series of ceramides derived from sphingosin with deuterated acyl chains with chain lenght 4C, 16C and 24C and their study using Fourier transform infrared spectroscopy to understand the behaviour of ceramides in SC and their structure-activity relationships. The study of the synthesized ceramides using ATR-FTIR spectroscopy revealed that, at skin temperature, lipid chains are arranged in orthorhombic subcell, mostly with all-trans conformation. While the CerNS24 prefers extended conformation with its acyl associated with the acyl of LA and cholesterol associated with the sphingosin chain in...
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