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    Wyświetlanie 1-10 z 10
    Tytuł:
    Proteolityczny kombinat i jego regulatory
    The proteolytic machinery and its regulators
    Autorzy:
    Stój, J.
    Karpowicz, P.
    Tematy:
    proteasom
    system ubikwityno-proteasomalny
    inhibitor
    allosteryczność
    proteasome
    ubiquitin-proteasome system
    allostery
    Pokaż więcej
    Wydawca:
    Polskie Towarzystwo Chemiczne
    Powiązania:
    https://bibliotekanauki.pl/articles/171680.pdf  Link otwiera się w nowym oknie
    Opis:
    One of the proteolytic pathways existing in a cell is ubiquitin- proteasome system (UPS). This highly organized and ATP-dependent system is based on the multifunctional enzyme – the proteasome. Ubiquitin in this pathway plays a role of a tag which marks proteins intended for destruction. Ubiquitylated proteins are recognized and degraded by the 26S proteasome. It consists of a cylindrical-shaped proteolytic core – the proteasome 20S, and attached to it regulatory particles 19S (Fig. 2). The core is composed of four rings, each of them formed by seven subunits. The inner â-rings harbour active sites (in Eukaryota two of each kind: chymotrypsin-like (ChT-L), trypsin-like (T-L) and peptidylglutamyl (PGPH)). The outer, á-rings create a gated channel leading to the catalytic chamber [8]. In a latent proteasome the gate is closed by tightly packed N-terminal residues of á subunits (Fig. 4). Due to such architecture the active sites of the proteasome are not freely available for the substrates. An opening of the gate in physiological conditions occurs after binding the activators such as 11S, 19S or PA200. By catalysing degradation of proteins, the UPS is deeply involved in regulation of cellular physiology. It is also involved in removing of misfolded or damaged proteins and supports the immune system by generating antigenic peptides. Defects in functioning of this proteolytic system play a causal role in the development of a number of diseases, including inflammation, neurodegenerative diseases and various cancers [2–6] what is the reason why the proteasome has become an important therapeutic target. Detailed information about the structure, catalytic activities and mechanisms of functioning of the different proteasome complexes existing in cells is essential to understand their role in organisms as well as to develop new compounds which may find pharmaceutical application.
    Dostawca treści:
    Biblioteka Nauki
    Artykuł
    Tytuł:
    Pioglitazone, a PPAR-gamma ligand, exerts cytostatic/cytotoxic effects against cancer cells, that do not result from inhibition of proteasome
    Autorzy:
    Mrówka, Piotr
    Głodkowska, Eliza
    Młynarczuk-Biały, Izabela
    Biały, Łukasz
    Kuckelkorn, Ulrike
    Nowis, Dominika
    Makowski, Marcin
    Legat, Magdalena
    Gołąb, Jakub
    Tematy:
    peroxisome proliferator-activated receptor-gamma
    thiazolidinediones
    proteasome
    pioglitazone
    Pokaż więcej
    Wydawca:
    Polskie Towarzystwo Biochemiczne
    Powiązania:
    https://bibliotekanauki.pl/articles/1040817.pdf  Link otwiera się w nowym oknie
    Opis:
    Thiazolidinediones are oral antidiabetic agents that activate peroxisome proliferator-activated receptor-gamma (PPAR-γ) and exert potent antioxidant and anti-inflammatory properties. It has also been shown that PPAR-γ agonists induce G0/G1 arrest and apoptosis of malignant cells. Some of these effects have been suggested to result from inhibition of proteasome activity in target cells. The aim of our studies was to critically evaluate the cytostatic/cytotoxic effects of one of thiazolidinediones (pioglitazone) and its influence on proteasome activity. Pioglitazone exerted dose-dependent cytostatic/cytotoxic effects in MIA PaCa-2 cells. Incubation of tumor cells with pioglitazone resulted in increased levels of p53 and p27 and decreased levels of cyclin D1. Accumulation of polyubiquitinated proteins within cells incubated with pioglitazone suggested dysfunction of proteasome activity. However, we did not observe any influence of pioglitazone on the activity of isolated proteasome and on the proteolytic activity in lysates of pioglitazone-treated MIA PaCa-2 cells. Further, treatment with pioglitazone did not cause an accumulation of fluorescent proteasome substrates in transfected HeLa cells expressing unstable GFP variants. Our results indicate that pioglitazone does not act as a direct or indirect proteasome inhibitor.
    Dostawca treści:
    Biblioteka Nauki
    Artykuł
    Tytuł:
    Slowing down aging from within: mechanistic aspects of anti-aging hormetic effects of mild heat stress on human cells.
    Autorzy:
    Rattan, Suresh
    Gonzalez-Dosal, Regina
    Nielsen, Elise
    Kraft, David
    Weibel, Jens
    Kahns, Søren
    Tematy:
    aging
    signal transduction
    anti-aging
    longevity
    proteasome
    heat shock
    Pokaż więcej
    Wydawca:
    Polskie Towarzystwo Biochemiczne
    Powiązania:
    https://bibliotekanauki.pl/articles/1043285.pdf  Link otwiera się w nowym oknie
    Opis:
    Since aging is primarily the result of a failure of maintenance and repair mechanisms, various approaches are being developed in order to stimulate these pathways and modulate the process of aging. One such approach, termed hormesis, involves challenging cells and organisms by mild stress that often results in anti-aging and life prolonging effects. In a series of experimental studies, we have reported that repeated mild heat stress (RMHS) has anti-aging hormetic effects on growth and various cellular and biochemical characteristics of human skin fibroblasts undergoing aging in vitro. These beneficial effects of repeated challenge include the maintenance of stress protein profile, reduction in the accumulation of oxidatively and glycoxidatively damaged proteins, stimulation of the proteasomal activities for the degradation of abnormal proteins, improved cellular resistance to other stresses, and enhanced levels of cellular antioxidant ability. In order to elucidate the molecular mechanisms of hormetic effects of RMHS, we are now undertaking studies on signal transduction pathways, energy production and utilisation kinetics, and the proteomic analysis of patterns of proteins synthesised and their posttranslational modifications in various types of human cells undergoing cellular aging in vitro. Human applications of hormesis include early intervention and modulation of the aging process to prevent or delay the onset of age-related conditions, such as sarcopenia, Alzheimer's disease, Parkinson's disease, cataracts and osteoporosis.
    Dostawca treści:
    Biblioteka Nauki
    Artykuł
    Tytuł:
    "Research on animal model of Parkinsons disease induced by intracerebral injection with proteasome inhibitor - lactacystin"
    "Badania nad zwierzęcym modelem choroby Parkinsona indukowanym domózgowym podaniem inhibitora proteasomu - laktacystyny"
    Autorzy:
    Dobrzański, Grzegorz
    Opis:
    Choroba Parkinsona jest nieuleczalną, postępującą chorobą neurodegeneracyjną. Jedyne dostępne leki wykazują wyłącznie właściwości symptomatyczne, łagodząc objawy choroby. W celu opracowania nowych leków o potencjale terapeutycznym wykorzystuje się zwierzęce modele choroby Parkinsona. Obecnie prowadzi się badania nad modelami, które najwierniej odzwierciedlają patogenezę choroby. Jednym z nich wydaje się model oparty o zahamowanie proteasomu.Celem prezentowanej pracy było sprawdzenie, czy po jednostronnym podaniu laktacystyny (10 μg/4μl), nieodwracalnego inhibitora proteasomu, do pęczka przyśrodkowego przodomózgowia (MFB) szczura dochodzi do wystąpienia charakterystycznych cech parkinsonizmu (deficytów behawioralnych i zmian biochemicznych). Zbadano katalepsję oraz zachowania rotacyjne wywołane amfetaminą (5 mg/kg) i apomorfiną (0,25 mg/kg). Po dekapitacji szczurów oszacowano poziom dopaminy i innych neuroprzekaźników w prążkowiu i istocie czarnej oraz sprawdzono poziom ekspresji mRNA dla proenkefaliny w prążkowiu.Wykazano katalepsję u szczurów w 1. i 3. dniu po podaniu laktacystyny, która zanikała po 7. dniu od podania toksyny. Zaobserwowano nasilone rotacje ipsilateralne wywołane podaniem amfetaminy oraz brak rotacji kontralateralnych wywołanych podaniem apomorfiny, co sugeruje odmienny w porównaniu do innych modeli mechanizm neurodegeneracyjny laktacystyny. Po raz pierwszy w badanym modelu stwierdzono wzrost ekspresji mRNA dla proenkefaliny w prążkowiu, sugerujący wzrost aktywności „szlaku pośredniego” wychodzącego z prążkowia. Pokazano, że laktacystyna powoduje wysoki spadek poziomu dopaminy w prążkowiu (88%) oraz umiarkowany w istocie czarnej (69%). Otrzymane wyniki podają jednak wysoki poziom zasadności modelu laktacystynowego wywołanego jednostronnym podaniem do MFB w wątpliwość.
    Parkinson's disease is incurable, progressive and degenerative disorder of central nervous system. Unfortunately, drugs being used to treat Parkinson's disease demonstrate only symptomatic effects, and temporarily alleviate motor symptoms. Animal models of Parkinson's disease are being used to investigate new anti-parkinsonian drugs. Nowadays, scientists make an attempt to build animal models that mimic pathogenesis of Parkinson's disease accurately. The animal model based on inhibition of the proteasome seems to be promising.The aim of the study was to determine if unilateral injection with irreversible proteasome inhibitor, lactacystin (10 μg/4μl), into the rat medial forebrain bundle (MFB) can induce parkinsonian-like symptoms (motor deficits as well as biochemical changes). Rats were tested for catalepsy and rotational behavior induced by amphetamine (5 mg/kg) and apomorphine (0.25 mg/kg). After obtaining behavioral data, rats were killed by decapitation and the levels of dopamine and other neurotransmitters in the substantia nigra and striatum were assayed. Striatal proenkephalin mRNA expression was also determined.Lactacystin evoked catalepsy on the first and third day after injection that decreased starting on seventh day after surgery. High number of ipsilatetral rotations induced by amphetamine and no contralateral rotations induced by apomorphine were demonstrated, what can indicate the difference in mechanism between lactacystin and other toxins used for modelling Parkinson's disease. For the first time increased striatal proenkephalin mRNA expression was found in lactacystin-lesioned rats, indicating hyperactivation of striatal "indirect" pathway. Lactacystin induced high dopamine decrease in striatum (88%) and modest decrease in substantia nigra (69%). All data indicates moderate validity of animal model of Parkinson's disease induced by unilateral injections with lactacystin into medial forebrain bundle.
    Dostawca treści:
    Repozytorium Uniwersytetu Jagiellońskiego
    Inne
    Tytuł:
    Synthesis of Gly-AMC, as a fluorogenic substrate for determination of USP2 inhibitors activity.
    Synteza fluorofora Gly-AMC, jako znacznika w testach aktywności potencjalnych inhibitorów białka USP2
    Autorzy:
    Profic, Anna
    Opis:
    Cyklina D1 to białko pełniące bardzo ważną funkcję w regulowaniu cyklu komórkowego przy przejściu komórki z fazy G1 do fazy S. Nadmierna ekspresja tego białka prowadzi do zmian nowotworowych m.in. piersi, trzustki, jelita grubego, płuc oraz układu chłonnego. Za degradację cykliny D1 odpowiedzialny jest System Ubikwityna-Proteasom. Odrębną rolę w tym procesie odgrywa enzym deubikwitynujący Specyficzna Proteaza dla Ubikwityny 2 (USP2), która nie dopuszcza do usunięcia cykliny D1 z komórki. Znalezienie inhibitora hamującego aktywność białka USP2 spowodowałoby zatrzymanie procesu kumulowania cykliny D1 w komórkach, a co za tym idzie możliwość leczenia licznych typów chorób nowotworowych. Powinowactwo potencjalnych inhibitorów do białka USP2 można badać między innymi w testach aktywności, które wykorzystują zjawisko fluorescencji znacznika AMC, uwolnionego z kompleksu Ub-AMC, w wyniku reakcji enzymatycznej. Niezbędny, dla tej metody, kompleks można otrzymać w wyniku reakcji pochodnej ubikwityny ze związkiem HCl•Gly-AMC. W niniejszej pracy przedstawiono metodę pięcioetapowej syntezy związku HCl∙Gly-AMC, gdzie jako produktu wyjściowego użyto m-aminafenolu. Otrzymany produkt pośredni 7-amino-4-metylokumarynę sprzężono z Boc-Gly, aby następnie w końcowej reakcji uzyskać HCl∙Gly-AMC.
    Cyclin D1 is a protein, that performs regulatory functions of the cell cycle at the transition state from G1 into S phase. Overexpression of the protein may result in cancer of breast, pancreas, colon, lung and lymphomas. Ubiquitin-Proteasome System is responsible for degradation of cyclin D1. Counter role in the process is played by deubiquitinating enzymes as Specific Protease for Ubiquitin 2 (USP2). Overexpression of USP2 promotes cyclin D1 deubiquitination and promotes its stability. Finding a small-molecule compound that would inhibit the activity of USP2, could stop the accumulation of cyclin D1 in the cells and help in many types of cancer treatment. The activity of potential inhibitors against USP2 can be deterred in assay experiments by measuring level of Gly-AMC fluorescence. The marker is released from the complex of Ub-Gly-AMC as a product of an enzymatic reaction catalyzed by USP2. Ub-Gly-AMC complex essential for the binding affinity tests, shall obtained by reacting an aldehyde derivative of ubiquitin with compound HCl ∙ Gly-AMC. The purpose of the following thesis was to introduce a five-step synthesis of HCl ∙ Gly-AMC reagent.
    Dostawca treści:
    Repozytorium Uniwersytetu Jagiellońskiego
    Inne
    Tytuł:
    Nienaturalne aminokwasy jako strategia do otrzymywania substratów, inhibitorów i niskocząsteczkowych sond aktywności dla enzymów proteolitycznych
    Unnatural amino acids as achemical tool for the development of protease substrates, inhibitors and activity - baseproblems
    Autorzy:
    Poręba, Marcin
    Kasperkiewicz-Wasilewska, Paulina
    Rut, Wioletta
    Drąg, Marcin
    Tematy:
    proteolytic enzymes
    substrate specificity
    unnatural amino acids
    substrates
    inhibitors
    activity-based probes
    caspases
    cathepsins
    neuthrophil serine proteases
    proteasome
    SARS-CoV-2 proteases
    enzymy proteolityczne
    specyficzność substratowa
    nienaturalne aminokwasy
    niskocząsteczkowe sondy aktywności
    kaspazy
    katepsyny
    proteasom
    proteazy wirusa SARS-CoV-2
    Pokaż więcej
    Wydawca:
    Polskie Towarzystwo Chemiczne
    Powiązania:
    https://bibliotekanauki.pl/articles/2200587.pdf  Link otwiera się w nowym oknie
    Opis:
    Proteolytic enzymes are molecular scissors that are responsible for the amide bond breakdown in peptide and protein substrates. Over the years, the view on proteases has been considerably changed from non-specific digestive enzymes to sophisticated biocatalysts, which by performing limited proteolysis control virtually all biological processes. In order to better understand how proteases work and what are their biologically relevant target substrates, it is indispensable to determine their catalytic preferences. This knowledge can be further utilized to develop selective substrates, inhibitors and activity-based probes (ABPs) enabling the monitoring of proteases activity in various settings, from in vitro analysis on recombinant enzymes or cell lysates to ex vivo and in vivo imaging at the single cell level. Among many chemical-based approaches that have been developed and applied over the years, the Hybrid Combinatorial Substrate Library (HyCoSuL) technology has emerged as one of the most powerful one. HyCoSuL is a combinatorial peptide-based library of fluorogenic substrates, that comprise natural and unnatural amino acids, that can deeply explore the chemical space in proteases active site, providing a structural framework for the development of highly-selective chemical tools. In this review we present the most prominent examples of proteolytic enzymes that have been profiled with HyCoSuL approach yielding selective substrates, potent inhibitors, and very sensitive activity-based probes.
    Dostawca treści:
    Biblioteka Nauki
    Artykuł
    Tytuł:
    Aminokwasy, glikany, peptydy i białka w ścieżkach diagnostycznych i terapeutycznych chorób cywilizacyjnych XXI wieku : projektowanie i charakterystyka fizykochemiczna oraz strukturalna
    Amino acids, glycans, peptides and proteins in the diagnostic and therapeutic pathways of the 21st century civilization diseases : design, physicochemical and structural characterisation
    Autorzy:
    Bylińska, Irena
    Dzierżyńska, Maria
    Giżyńska, Małgorzata
    Guzow, Katarzyna
    Jankowska, Elżbieta
    Jurczak, Przemysław
    Kaczyński, Zbigniew
    Karska, Natalia
    Kowalczyk, Agnieszka
    Kuncewicz, Katarzyna
    Orlikowska, Marta
    Sawicka, Justyna
    Spodzieja, Marta
    Szpakowska, Nikola
    Szymańska, Aneta
    Wieczerzak, Ewa
    Witkowska, Julia
    Rodziewicz-Motowidło, Sylwia
    Tematy:
    fluorophores
    fluorescence spectroscopy
    antimicrobial activity
    anticancer activity
    Cystapep
    Stahylococcus aureus
    antimicrobial compounds
    amyloidogenic protein
    mutagenesis
    fibrilization
    proteasome
    aging
    neurodegeneration
    self-assembling peptides
    tissue engineering
    biomaterials
    immune checkpoints
    peptide inhibitors
    immunotherapy
    ligands of TAP protein
    viral diseases
    NMR structure of the UL49.5 protein
    glycans
    glycoconjugates
    fluorofory
    spektroskopia fluorescencyjna
    aktywność przeciwdrobnoustrojowa
    aktywność antynowotworowa
    Staphylococcus aureus
    związki przeciwbakteryjne
    białko amyloidogenne
    mutageneza
    fibrylizacja
    proteasom
    procesy starzeniowe
    neurodegeneracja
    peptydy samoorganizujące
    inżynieria tkankowa
    biomateriały
    punkty kontrolne układu immunologicznego
    inhibitory peptydowe
    immunoterapia
    ligandy białka TAP
    choroby wirusowe,
    struktura NMR białka UL49.5
    glikany
    glikokoniugaty
    Pokaż więcej
    Wydawca:
    Polskie Towarzystwo Chemiczne
    Powiązania:
    https://bibliotekanauki.pl/articles/2200549.pdf  Link otwiera się w nowym oknie
    Opis:
    The civilization diseases of the 21st century are non-infectious disorders, affecting a large part of modern society. They are associated with the significant development of industry and technology, and hence with environmental pollution and an unhealthy lifestyle. These factors have led to the development of many civilization diseases, which currently include: cardiovascular diseases, respiratory diseases, diabetes, obesity, malignant tumors, gastrointestinal diseases, mental disorders and allergic diseases. The development of technologies, including modern therapies and new drugs, resulted in increase in life expectancy. This creates a global problem of an aging population with an increasing number of diseases of the old age, i.e. dementias. In addition, sedentary lifestyles and changing diets are the reasons why more and more people develop metabolic diseases, as well as neurological and cognitive disorders characterized by progressive damage to nerve cells and dementia. Currently, problem on a global scale is also the growing resistance to existing antimicrobial drugs. Therefore, the scientists face many challenges related to searching for the causes of these diseases, their diagnosis and treatment. Scientific research conducted at the Department of Biomedical Chemistry at the Faculty of Chemistry of the University of Gdańsk is part of this research trend. In this publication, we discuss various research topics with the long-term aim of solving the problems associated with the diseases mentioned above. The following chapters are dedicated to (i) looking for new effective fluorophores with diagnostic and anti-cancer activity; (ii) designing of new compounds with antibacterial and antiviral activity and their synthesis; (iii) investigating the mechanisms of amyloid deposit formation by human cystatin C and possibilities of inhibition of this process; (iv) designing and studies of compounds activating the proteasome with the potential to suppress the development of neurodegenerative diseases; (v) designing peptide fibrils and hydrogels as drug carriers; (vi) searching for peptide inhibitors of immune checkpoint as potential drugs for immunotherapy; (vii) studying the mechanism of action of selected herpesviruses by determining the structure of viral proteins and (viii) studying the composition of natural glycans and glycoconjugates in order to better understand the mechanisms of interaction of bacteria with the environment or with the host.
    Dostawca treści:
    Biblioteka Nauki
    Artykuł
      Wyświetlanie 1-10 z 10

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