Mitochondrial physiology

As the knowledge base and importance of mitochondrial physiology to evolution, health and disease expands, the necessity for harmonizing the terminology concerning mitochondrial respiratory states and rates has become increasingly apparent. The chemiosmotic theory establishes the mechanism of energy transformation and coupling in oxidative phosphorylation. The unifying concept of the protonmotive force provides the framework for developing a consistent theoretical foundation of mitochondrial physiology and bioenergetics. We follow the latest SI guidelines and those of the International Union of Pure and Applied Chemistry (IUPAC) on terminology in physical chemistry, extended by considerations of open systems and thermodynamics of irreversible processes. The concept-driven constructive terminology incorporates the meaning of each quantity and aligns concepts and symbols with the nomenclature of classical bioenergetics. We endeavour to provide a balanced view of mitochondrial respiratory control and a critical discussion on reporting data of mitochondrial respiration in terms of metabolic flows and fluxes. Uniform standards for evaluation of respiratory states and rates will ultimately contribute to reproducibility between laboratories and thus support the development of data repositories of mitochondrial respiratory function in species, tissues, and cells. Clarity of concept and consistency of nomenclature facilitate effective transdisciplinary communication, education, and ultimately further discovery

Mitochondrial physiology

As the knowledge base and importance of mitochondrial physiology to evolution, health and disease expands, the necessity for harmonizing the terminology concerning mitochondrial respiratory states and rates has become increasingly apparent. The chemiosmotic theory establishes the mechanism of energy transformation and coupling in oxidative phosphorylation. The unifying concept of the protonmotive force provides the framework for developing a consistent theoretical foundation of mitochondrial physiology and bioenergetics. We follow the latest SI guidelines and those of the International Union of Pure and Applied Chemistry (IUPAC) on terminology in physical chemistry, extended by considerations of open systems and thermodynamics of irreversible processes. The concept-driven constructive terminology incorporates the meaning of each quantity and aligns concepts and symbols with the nomenclature of classical bioenergetics. We endeavour to provide a balanced view of mitochondrial respiratory control and a critical discussion on reporting data of mitochondrial respiration in terms of metabolic flows and fluxes. Uniform standards for evaluation of respiratory states and rates will ultimately contribute to reproducibility between laboratories and thus support the development of data repositories of mitochondrial respiratory function in species, tissues, and cells. Clarity of concept and consistency of nomenclature facilitate effective transdisciplinary communication, education, and ultimately further discovery

Tourism development and recreation of Bochnia district

Powiat bocheński ze względu na doskonałe położenie, unikatowe w skali światowej zabytki, bogactwo krajobrazu, bazę turystyczną i dobrze rozwinięte szlaki komunikacyjne stanowi znakomite miejsce do wypoczynku i rekreacji. Spośród walorów antropogenicznych najwięcej turystów odwiedza jeden z najstarszych zakładów przemysłowych w Europie czyli Kopalnię Soli w Bochni. Równie cennym zabytkiem jest Zamek Kmitów i Lubomirskich. Wspólnie stanowią one główny cel wycieczek turystycznych w powiecie bocheńskim. Należy pamiętać także o niezwykle cennych walorach krajobrazowych powiatu, których wykorzystanie w celach rozwoju turystyki i rekreacji wiąże się z ożywieniem gospodarczym, a także utworzeniem nowych miejsc pracy na tych terenach. Głównym celem badań było scharakteryzowanie oraz zestawienie rzeczywistego rozmieszczenia zagospodarowania turystycznego powiatu bocheńskiego. Dokonano w tym celu inwentaryzacji infrastruktury turystycznej w poszczególnych gminach oraz miastach powiatu bocheńskiego. Praca liczy sześć rozdziałów. Rozdział pierwszy obejmuje krótkie przedstawienie powiatu bocheńskiego, jego położenie oraz podział administracyjny. Rozdział drugi zawiera omówienie położenia fizyczno – geograficznego wraz z budową geologiczną oraz hydrografię, warunki glebowe, ukształtowanie terenu, a także warunki klimatyczno – meteorologiczne powiatu bocheńskiego. W rozdziale trzecim oraz czwartym przedstawiono główne elementy sytuacji społeczno – gospodarczej oraz najważniejsze wydarzenia historyczne w powiecie bocheńskim. W rozdziale piątym opisano walory przyrodnicze i antropogeniczne powiatu z podziałem na zabytki architektury, miejsca kultu religijnego oraz wydarzenia i imprezy kulturalne. W ostatnim rozdziale poddano analizie istniejącą w powiecie bazę noclegową, gastronomiczną, towarzyszącą oraz dostępność komunikacyjną.Bochnia district because of its excellent location, priceless monuments in the world, spectacular landscapes, tourist base and well-developed routes network is an excellent place to take a rest and recreation. Among the advantages of anthropogenic most tourists visit one of the oldest industrial companies in Europe that is the Salt Mine in Bochnia. As valuable as monument is the Kmita and Lubomirski Castle. Together they determine the main tourist destination in the Bochnia district. We have to keep this extremely valuable natural beauty of the district in mind, to be used for the development of tourism and recreation associated with the economic recovery and the creation of new jobs in this area.The main objective of this study was to characterize and a list of the actual distribution of the county tourist development of Bochnia district. For this purpose inventory of the tourism infrastructure in the different municipalities and cities in the Bochnia district has been made. Work consists of six chapters. The first chapter includes short introduction of the Bochnia district, its location and the administrative division. The second chapter contain geographical position and geological structure as well as hydrography, soil conditions, lay of the land, meteorology and climatic circumstances of Bochnia district. In the third and fourth chapter presents the main elements of the socio - economic situation and the most important historical events in the Bochnia district. The fifth chapter describes breakdown of architectural monuments, religious places, and cultural events. The last chapter presents accommodation base, gastronomic accompanying base and accessibility of the communication existing in the district

Search for new thymidine phosphorylase inhibitors using molecular modelling methods.

Fosforylaza tymidyny (TP) odgrywa ważną rolę w patogenezie chorób nowotworowych. W części teoretycznej niniejszej pracy scharakteryzowano występowanie, funkcje fizjologiczne oraz mechanizmy, poprzez które TP promuje rozwój nowotworów. Na podstawie przeglądu literatury przedstawiono znane inhibitory TP o różnej budowie chemicznej. Część eksperymentalna zawiera opis poszukiwania nowych inhibitorów przy pomocy metod modelowania cząsteczkowego. W celu poznania budowy TP, wykonano analizę sekwencji aminokwasowych. Dostępne struktury krystaliczne uzyskane z trzech różnych organizmów porównano za pomocy programu PyMOL. Następnie przeprowadzono walidację metody dokowania korzystając z pakietu Schrӧdingera. Przygotowane w programie LigPrep ligandy dokowano w module Glide do 7 struktur TP. Wybraną metodę dokowania oceniono na podstawie współczynników wzbogacenia bazy. Następnie przeprowadzono wirtualny skrining ligandów z bazy ZINC oraz własnej bazy związków. Wyniki analizowano w programach Maestro oraz PyMOL. Otrzymano 330 ligandów o korzystnej wartości GlideScore. Analiza wizualna pozwoliła na wybór 26 związków o różnej budowie chemicznej, które tworzyły specyficzne oddziaływania w miejscu wiążącym ludzkiej TP. Przy pomocy serwisu SwissADME przewidziano właściwości fizykochemiczne i farmakokinetyczne wybranych związków. Wybrano 5 hitów o najlepszym dopasowaniu do miejsca aktywnego enzymu oraz optymalnych właściwościach. Są to pochodne uracylu oraz hydantoiny, których aktywność będzie oceniana w przyszłych badaniach in vitro.Thymidine phosphorylase (TP) plays an important role in pathogenesis of cancer. In the theoretical part the occurrence, physiological functions and the mechanisms by which TP promote tumour progression were characterized. Based on the literature studies, known TP inhibitors of different chemical structures were presented. The experimental part contains a description of developing new thymidine phosphorylase inhibitors due to molecular modelling methods. In order to understand the structure of TP, an analysis of amino acid sequences was performed. Available crystal structures obtained from three different organisms were compared using the PyMOL software. Next, the docking method was validated using Schrӧdinger Suite. The ligands prepared in LigPrep were docked to the 7 TP structures with Glide module. Chosen docking method was assessed based on the enrichment factors. Then a virtual screening of ligands from ZINC and own data bases was performed. Results were analysed in Maestro and PyMOL.330 ligands with favourable GlideScore values were obtained. Visual analysis allowed to choose 26 ligands of different chemical structures, which created specific interactions in the binding site of human TP. For selected compounds the physicochemical and pharmacokinetic properties were predicted with SwissADME website. 5 hits with the best fit to the enzyme active site and optimal properties were selected. They are derivatives of uracil and hydantoin, their activity will be tested in vitro in the future projects

Structural Studies of the Taurine Transporter: A Potential Biological Target from the GABA Transporter Subfamily in Cancer Therapy

The taurine transporter (TauT, SLC6A6) is a member of the solute carrier 6 (SLC6) family, which plays multiple physiological roles. The SLC6 family is divided into four subfamilies: GABA (γ-aminobutyric acid), monoamine, glycine and neutral amino acid transporters. Proteins from the GABA group, including the taurine transporter, are primarily considered therapeutic targets for treating central nervous system disorders. However, recent studies have suggested that inhibitors of SLC6A6 could also serve as anticancer agents. Overexpression of TauT has been associated with the progression of colon and gastric cancer. The pool of known ligands of this transporter is limited and the exact spatial structure of taurine transporter remains unsolved. Understanding its structure could aid in the development of novel inhibitors. Therefore, we utilized homology modelling techniques to create models of TauT. Docking studies and molecular dynamics simulations were conducted to describe protein–ligand interactions. We compared the obtained information for TauT with literature data on other members of the GABA transporter group. Our in silico analysis allowed us to characterize the transporter structure and point out amino acids crucial for ligand binding: Glu406, Gly62 and Tyr138. The significance of selected residues was confirmed through structural studies of mutants. These results will aid in the development of novel taurine transporter inhibitors, which can be explored as anticancer agents

Design, synthesis, and in vitro antiproliferative activity of hydantoin and purine derivatives with the 4-acetylphenylpiperazinylalkyl moiety

Cancer represents one of the most serious health problems and the second leading cause of death around the world. Heterocycles, due to their prevalence in nature as well as their structural and chemical diversity, play an immensely important role in anti-cancer drug discovery. In this paper, a series of hydantoin and purine derivatives containing a 4-acetylphenylpiperazinylalkyl moiety were designed, synthesized, and biologically evaluated for their anticancer activity on selected cancer cell lines (PC3, SW480, SW620). Compound 4, a derivative of 3′,4′-dihydro-2′H-spiro[imidazolidine-4,1′-naphthalene]-2,5-dione, was the most effective against SW480, SW620, and PC3 cancer cell lines. Moreover, 4 has high tumor-targeting selectivity. Based on docking studies, it was concluded that R isomers of 3′,4′-dihydro-2′H-spiro[imidazolidine-4,1′-naphthalene]-2,5-dione could be further studied as promising scaffolds for the development of thymidine phosphorylase inhibitors

Biphenylalkoxyamine derivatives : histamine H3 receptor ligands with butyrylcholinesterase inhibitory activity

Neurodegenerative diseases, e.g., Alzheimer’s disease (AD), are a key health problem in the aging population. The lack of effective therapy and diagnostics does not help to improve this situation. It is thought that ligands influencing multiple but interconnected targets can contribute to a desired pharmacological effect in these complex illnesses. Histamine H3 receptors (H3Rs) play an important role in the brain, influencing the release of important neurotransmitters, such as acetylcholine. Compounds blocking their activity can increase the level of these neurotransmitters. Cholinesterases (acetyl- and butyrylcholinesterase) are responsible for the hydrolysis of acetylcholine and inactivation of the neurotransmitter. Increased activity of these enzymes, especially butyrylcholinesterase (BuChE), is observed in neurodegenerative diseases. Currently, cholinesterase inhibitors: donepezil, rivastigmine and galantamine are used in the symptomatic treatment of AD. Thus, compounds simultaneously blocking H3R and inhibiting cholinesterases could be a promising treatment for AD. Herein, we describe the BuChE inhibitory activity of H3R ligands. Most of these compounds show high affinity for human H3R (Ki < 150 nM) and submicromolar inhibition of BuChE (IC50 < 1 µM). Among all the tested compounds, 19 (E153, 1-(5-([1,1′-biphenyl]-4-yloxy)pentyl)azepane) exhibited the most promising in vitro affinity for human H3R, with a Ki value of 33.9 nM, and for equine serum BuChE, with an IC50 of 590 nM. Moreover, 19 (E153) showed inhibitory activity towards human MAO B with an IC50 of 243 nM. Furthermore, in vivo studies using the Passive Avoidance Task showed that compound 19 (E153) effectively alleviated memory deficits caused by scopolamine. Taken together, these findings suggest that compound 19 can be a lead structure for developing new anti-AD agents