8 research outputs found
Računovodske informacije za odločanje o financiranju s poudarkom na odločitvah o uporabi denarnih sredstev : diplomsko delo
Synthesis and evaluation of new N-alkyl amides as potential selective inhibitors of butyrylcholinesterase
Raziskovanje novih zdravilnih učinkovin za zdravljenje Alzheimerjeve bolezni (AB) kot vodilnega vzroka demence pridobiva na pomenu. Obstoječa zdravila za simptomatsko zdravljenje AB, ki v večini spadajo v skupino zaviralcev encima acetilholin esteraze (AChE), delujejo kratkotrajno ter so primerna predvsem za zdravljenje v zgodnjih fazah bolezni. Pri napredovani obliki AB pride do povišanja aktivnosti in koncentracije encima butirilholin esteraze (BChE), ki je tako obetavna tarča za načrtovanje novih učinkovin za lajšanje simptomov v poznejših fazah AB.
V magistrski nalogi smo se osredotočili na raziskovanje novih učinkovin, ki so selektivne za BChE in posledično izkazujejo možnost zdravljenja tudi v kasnejših fazah bolezni. V ta namen smo sintetizirali različne ciljne amide, ki so potencialni selektivni zaviralci encima BChE. Te smo sintetizirali na podlagi predlagane knjižnice amidov, ki je bila generirana na osnovi spojine vodnice z molekulskim sidranjem. Kot izhodiščno molekulo smo uporabili aminokislino L-triptofan, pri kateri smo na amino skupino uvedli različno dolge alkilne skupine, s karboksilno skupino pa smo tvorili amidno vez s pripenjanjem izbranih aminov. Pripravljene spojine smo v celoti okarakterizirali in ovrednotili njihovo aktivnost in vitro na encimih hBChE in hAChE z uporabo Ellmanove metode.
Sintetizirali smo 11 novih za BChE selektivnih triptofanskih α-aminoamidov s srednjo zaviralno koncentracijo v nanomolarnem območju. Najboljšo zaviralno aktivnost so imele spojine z etilnim distančnikom med cikloalkilnim obročem in amidno skupino na karboksilnem delu ter n-butilno ročko na aminskem delu L-triptofana. V seriji novih sintetiziranih zaviralcev je bila najmočnejši zaviralec spojina 11 s 23,1 nM srednjo zaviralno koncentracijo.
Zaradi preproste sinteze in dobljenih rezultatov biološkega testiranja lahko potrdimo, da spojine s triptofanskim ogrodjem predstavljajo primerno podlago za nadaljnjo optimizacijo do spojin vodnic pri načrtovanju novih zaviralcev BChE.Research of new active substances for the treatment of Alzheimer\u27s disease (AD), a leading cause of dementia, is gaining an importance. Existing symptomatic treatments, mostly consisting of acetylcholineesterase (AChE) inhibitors, have a short-term effect and are particularly suitable for treatment of early stages of the disease. With progression of AD, there is an increase in activity and concentration of the butyrylcholineesterase (BChE), which is therefore a promising target for the design of new active substances for symptomatic treatment in the later stages of AD.
In this master\u27s thesis we have focused on the research of novel agents that are selective for BChE and consequently demonstrate the possibility of treatment in the later stages of the disease. For that purpose, we synthesized various target amides, which are selective inhibitors of the BChE. These were synthesized on the basis of a proposed library of target amides, which was generated using lead compound and computational virtual screening.
The amino acid L-tryptophan was used as the starting molecule, to which various long alkyl groups were attached to the amine moiety. By attachment of selected amines, an amide bond was formed using the carboxyl group. The prepared compounds were fully characterized and their in vitro activity was evaluated on hBChE and hAChE enzymes using the Ellman method.
We synthesized 11 novel BChE-selective tryptophan α-aminoamides with a mean inhibitory concentrations in the nanomolar range. The compounds with the ethyl spacer between the simple cycloalkyl ring and the amide group on the carboxyl moiety, and the n-butyl handle on the amine moiety of L-tryptophan, showed the best inhibitory activity. In the series of new inhibitors, the strongest inhibitor was compound 11 with IC50 value of 23.1 nM.
Due to the simple synthesis and promising results of the bioassay, we can confirm that the tryptophan-based compounds provide a suitable basis for further optimization as lead compounds in the design of new BChE inhibitors
The effect of agonists and antagonists of CB1 and CB2 receptors on expression of some cytokines in lymphoid cell cultures developed from asthmatic patients
Astma je kronična vnetna bolezen dihal, pri kateri se pod vplivom različnih dražljajev zožijo dihalne poti, pojavi se njihovo kronično vnetje in nabiranje sluzi v bronhijih. Vse to vodi v oteženo dihanje, občutek stiskanja prsnega koša in kašljanja, predvsem sredi noči ali zgodaj zjutraj. V diplomski nalogi smo se osredotočili na ex vivo proučevanje endokanabinoidnega sistema pri imunskem odzivu bolnikov z astmo in predlagali alternative trenutnim načinom zdravljenja s protivnetnimi (ti. preprečevalci) in bronhodilatornimi (ti. olajševalci) zdravili. Zanimal nas je učinek agonistov in antagonistov kanabinoidnih receptorjev CB1 in CB2 na izražanje citokinov in obeh receptorjev. V ta namen smo v limfoidnih celičnih kulturah bolnikov z astmo in zdravih posameznikov izmerili izražanje genov CNR1, CNR2, IL4, IL5, IL6, IL8, IL10 in CSF2 v odvisnosti od tretiranja z različnimi sintetičnimi kanabinoidi.
Da bi ex vivo simulirali vnetno okolje smo celične kulture gojili v prisotnosti dejavnika tumorske nekroze-α (TNF), ki se je v različnih raziskavah izkazal kot pomemben posrednik vnetnega odgovora. Za najbolj optimalne rezultate gojenja celičnih kultur iz vzorcev astmatičnih bolnikov in zdravih posameznikov, smo najprej izvedli optimizacijo koncentracije uporabljenega TNF in časa njegove inkubacije ter optimalne koncentracije uporabljenih sintetičnih kanabinoidov, pri čemer nam je kot merilo služila stopnja izražanja genov. Med samo optimizacijo parametrov nismo potrdili predpostavljene odvisnosti izražanja CNR2 od učinkov TNF, zato načrtovanega tretiranja z njegovimi agonisti in antagonisti nismo izvedli. V celičnih kulturah tretiranih z ACEA (sintetični agonist receptorja CB1) smo pri vzorcih astmatičnih bolnikov izmerili povišano ekspresijo IL5 v primerjavi z netretiranimi celicami in celicami zdravih posameznikov. V astmatičnih vzorcih je bila povišina tudi ekspresija genov CNR1 in IL4 v primerjavi z zdravimi posamezniki, vendar ni bilo učinka ACEA. S tretiranjem celic z AM251 (sintetični antagonist receptorja CB1) smo potrdili, da učinki ACEA dejansko potekajo preko CB1 receptorja.
Iz dobljenih rezultatov je mogoče sklepati, da kanabinoidi z učinkom na izražanje citokinov lahko vplivajo na delovanje vnetnega procesa pri bolnikih obolelih za astmo, zato bi lahko v prihodnosti služili kot pomembne farmakološke učinkovine za zdravljenje astme.Asthma is a chronic inflammatory disease of the respiratory tract, in which, under the influence of different stimuli, airways narrow and chronic inflammation and the accumulation of mucus in the bronchi emerge. All this leads to shortness of breath, feeling of tightness of the chest, and coughing, particularly at night or early in the morning. In this thesis, we focused on ex vivo study of the endocannabinoid system (ECS) in the immune response of patients with asthma with the aim to explore its potential as a novel drug target and treatment procedures. If the involvement of ECS in asthma would be confirmed, alternatives to the current methods of treatment with anti-inflammatory and bronhodilatatory medicines could be developed. We were interested in the effect of agonists and antagonists of cannabinoid receptors (CB) 1 and 2 on the expression of selected cytokines and both receptors. In this manner, we measured gene expressions of CNR1, CNR2, IL4, IL5, IL6, IL8, IL10 and CSF2 in the lymphoid cell cultures of patients with asthma and healthy individuals as a function of treatment with synthetic cannabinoids.
In order to simulate an ex vivo inflammatory environment, cell cultures were grown in the presence of tumor necrosis factor-α (TNF), which already proved as a major mediator of the inflammatory response in a variety of studies. To achieve best results we first performed the optimization of TNF concentration and its incubation time together with the optimization of cannabinoid concentration, where the level of cytokine gene expressions served as a measure. During parameter optimization, we did not confirm the hypothesized dependence of CNR2 expression with TNF treatmenttherefore, we did not perform the planned treatment with its agonists and antagonists.
Results showed that in cell cultures treated with CB agonist expression of IL5 was elevated in cells of asthmatic patients in comparison with untreated asthmatic cells and the cells of healthy individuals. In comparison with healthy individuals, we found higher CNR1 and IL4 gene exspression, but there was no effect of CB1 agonist. The treatment of cells with CB1 antagonist, we confirmed that the effects of CB1 agonist actually took place via CB1 receptor.
From the obtained results it can be concluded that cannabinoids may affect the operation of the inflammatory process in patients suffering from asthma via cytokine genes expression. Components of ECS could therefore serve as an important pharmacological targets for future development of novel strategies for asthma
Sizing net-metering PV system in PV*SOL computer application
Od leta 2016 veljavna Uredba o samooskrbi z električno energijo, v Republiki Sloveniji nudi odlične pogoje za postavitev naprav za samooskrbo z električno energijo na podlagi neto merjenja (net-metering). Padajoče cene investicij, so znatno pripomogle k trendu postavitev lastnih mikro sončnih elektrarn. V projektnem delu sem predstavil solarne sisteme in komponente, kasneje pa prikazal dimenzioniranje, simuliranje in finančni izračun v programskem orodju PV*SOL.As of 2016 decree of self-supply with electricity came to life, Slovenia presents fantastic oppertunity for investing in grid connected solar photovoltaic systems. Decrease of costs greatly encouraged investors in building their own solar power plants. In my project I presented solar sistems and its components, and later sized, simulated and financially analyzed the system with computer applicataion PV*SOL
Statin-Associated Necrotizing Myopathy Leading to Acute Kidney Injury: A Case Report
Statins or 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors are a mainstay of cardiovascular disease therapy. In addition to their lipid-lowering capabilities, they exhibit several pleiotropic effects. Their adverse reactions such as myalgias are not uncommon, but in rare cases, the resulting rhabdomyolysis can be fatal. Recently, more insight has been brought into the pathogenesis of statin-induced rhabdomyolysis, and immune-mediated necrotizing myopathies are diagnosed more frequently. We present a case of a female patient who was on chronic rosuvastatin therapy and developed necrotizing myopathy. The disease progressed to acute kidney and liver injury. We discontinued the drug, started supportive measures, and initiated renal replacement therapy with a high cutoff dialysis membrane once. Her recovery was prompt, with a normal control electromyography 2 weeks after discharge