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The effect of long-term morphine and its withdrawal on selected signaling proteins in rat heart
Ilková, Karolina ; Novotný, Jiří (advisor) ; Černá, Věra (referee)
Morphine is considered the gold standard among analgesics in the treatment of severe pain due to its effects mediated by μ-opioid receptors. However, it also produces various side effects and poses a high risk of developing tolerance and dependence. The aim of this bachelor thesis is to contribute to the elucidation of the action of morphine at the molecular level in cardiac muscle. Changes of protein levels in key signaling molecules in the signaling cascade induced by morphine administration with increasing doses and subsequent abstinence for 24 hours, 1 month and 3 months were investigated. Specifically, these were adenosine A2b receptor, β2-adrenergic receptor, κ-opioid receptor, G protein subunits, GRK5 kinase, and β-arrestin 2. Data of changes in expression were obtained from cardiac tissue homogenates (left ventricle) by Western blot followed by immunodetection, captured on light-sensitive photofilms, and statistically evaluated by ANOVA. Morphine administration did not lead to statistically significant changes in G protein subunits, β- arrestin 2, GRK5 kinase, adenosine A2b receptor, β2-adrenergic receptor, or κ-opioid receptor in rat heart. Therefore in order to develop better and safer analgesics, there is a high necessity of understanding the underlying molecular mechanisms of morphine...
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Role of β-arrestin in μ-opioid and TRPV1 receptor signalling
Nagy Marková, Vendula ; Novotný, Jiří (advisor) ; Blahoš, Jaroslav (referee) ; Roubalová, Lenka (referee)
β-Arrestin belongs to the protein family which has a huge impact not only on GPCR signaling, but its role exceeds the function of the membrane channel, its own signaling cascade, or as a scaffold protein, etc. Here we aimed to study β-arrestin roles on the MOR behaviour in the plasma membrane or -opioid receptor (MOR) signaling and effect on adenylyl cyclase (AC) function using the siRNA to decrease the expression of β-arrestin isoforms. Furthermore, we focused on investigating the role of β-arrestin on the crosstalk between MOR and TRPV1 channels, which are important parts of pain transduction. For this purpose, we used HEK293 cells that stably expressed MOR-YFP or transiently transfected with TRPV1-CFP. We observed that both β-arrestin isoforms have an effect on the lateral mobility of MOR in the plasma membrane and the silencing of one or another β-arrestin isoforms abolishes the effect of MOR agonists to affect its diffusion in the plasma membrane. Interestingly, silencing of β-arrestin1 diminish the internalization of MOR induced by the endogenous agonist endomorphin-2. On the other hand, silencing of β-arrestin2 did not abolish the endomorphin-2 induced MOR internalization. Moreover, both isoforms exhibit a distinct impact on the inhibition of AC induced by the agonists of MOR....
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Designing and programming wireless lens control system
NOVOTNÝ, Jiří
This work focuses on designing and programming a product, that wirelessly controls the focus ring of a camera lens. The product is based on an Arduino nano programmable circuit board incorporating an ATmega328P microcontroller, that is used for all calculations, stores the whole code on a flash memory, controlling the inputs and outputs of an electronic components specifically a potentiometer, a buttons, a step motor, a motor driver and a wireless modules. The final product consists of two smaller devices, the transmitter, which is held by the user for sending information and the receiver controlling the motor. Both devices are powered by USB power banks. Programming and debugging take place in Arduino IDE. Designing and modelling parts e.g. spur gears and the case uses Blender. Final outcome aims to make cheaper, but equally efficient product as the commercial solution for this product.
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On relevant deformations in Open String Field Theory
Scheinpflug, Jaroslav ; Schnabl, Martin (advisor) ; Novotný, Jiří (referee)
String field theory takes string perturbation theory off-shell and since the different vacua of string theory are described by conformal field theories, it is tempting to use string field theory to describe conformal perturbation theory. We use open string field theory to reproduce the known leading order results of boundary conformal perturbation theory and we also perform the next-to-leading order calculation of the boundary degeneracy g for a generic theory. This is achieved by finding perturbative solutions to the classical equations of motion of open string field theory corresponding to weakly relevant deformations. The observables of conformal perturbation theory are then given by calculating the on-shell action or by invoking the Kudrna-Maccaferri-Schnabl correspondence. We also lay the groundwork for the investigation of the shift in the boundary spectrum. This work is largely based on the collaboration with Martin Schnabl [1].
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Psilocybin: the mechanism of action and therapeutic potential
Mintálová, Tímea ; Novotný, Jiří (advisor) ; Vejmola, Čestmír (referee)
Psilocybin is a psychoactive molecule derived from tryptamine precursors that is present in some mushrooms, especially those belonging to the Psilocybe genus. Its pharmacologically active metabolite, produced by dephosphorylation, is psilocin, which can cross the blood-brain barrier. It is believed that the psychedelic effects of psilocin result from its partial agonistic activities on 5-HT2A receptors, the main receptor subtype among serotonin G-protein-coupled receptors (GPCRs). Psilocin also binds to a number of other subtypes of these receptors, but the effects it has on these receptors have not been fully explored yet. Psilocybin has been studied for its potential use in treating anxiety, depression, and disorders caused by addictive substances when administered in concentrations sufficient to produce psychedelic effects. The pharmacological potential of psilocybin is without the risks of potential addiction or overdose compared to other psychoactive drugs such as cocaine, alcohol, methamphetamine, and others. Due to the increasing worldwide trend of addiction, overdose, and suicidal deaths, it is necessary to seek new therapeutic alternatives. However, it is also necessary to assess various contraindications that may limit the possibility of using psilocybin as a pharmacological therapy....
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The role of RNA demethylase FTO in differentiation, regulation of energy metabolism and sensitivity to streptozotocin of neuronal and glial cell models
Čočková, Zuzana ; Novotný, Jiří (advisor) ; Horák, Martin (referee) ; Balík, Aleš (referee)
Fat mass and obesity associated (FTO) demethylase is responsible for erasure of the most abundant epitranscriptomic mark in eukaryotic mRNA, the N6-methyladenosine (m6A) residue. Together with other m6A erasers, writers (methyltransferases) and readers it forms an m6A regulatory pathway that controls the amount, location and biological effect of m6A. The dynamic regulation of the brain's m6A methylome during neurodevelopment is essential for maintaining cerebral functions. In addition, preclinical research suggests that the m6A regulatory pathway regulates energy balance in a tissue- and cell type-specific manner. The FTO gene has been associated with lifelong risks of obesity and metabolic syndrome as well as regulation of total body energy intake and expenditure. However, little is understood about the function of the m6A pathway in control of brain energy metabolism. That is of interest in pursuit of understanding Alzheimer's disease, as this illness is characterized by profound disruptions in cerebral energy metabolism and mounting evidence suggests that disrupted brain bioenergetics may play a role in the disease's early genesis, before the appearance of clinical symptoms. In the present thesis we aimed to investigate the role of FTO in models of two brain cell types, neurons and astrocytes....
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The study of functional and pharmacological properties of glutamate receptors
Kysilov, Bohdan ; Vyklický, Ladislav (advisor) ; Valeš, Karel (referee) ; Novotný, Jiří (referee)
N-methyl-D-Aspartate receptors (NMDAR) are ionotropic glutamate receptors that are involved in the regulation of nearly every process in the brain. Therefore, even a subtle disturbance in NMDAR function may result in severe pathological consequences. Loss-of- function mutations in the NMDAR-encoding genes have been implicated in numerous neuropsychiatric disorders, including intellectual disability, developmental delay, schizophrenia, autism spectrum disorders, epilepsy, and movement disorders. Insufficient NMDAR function can be rectified by positive allosteric modulators, including neurosteroids; however, the mechanism underlying the potentiating effect of steroids is not well understood. By employing patch-clamp electrophysiology we assessed the effect of newly synthesized neurosteroid-like pregnane analogues on recombinant GluN1/GluN2B receptors. We demonstrated that compounds with short C3 residues, such as pregnanolone acetate (PA- Ace) and pregnanolone carboxylate (PA-Car), are negative modulators of NMDAR, whereas compounds with longer C3 residues, such as pregnanolone butyrate (PA-But) and epipregnanolone butyrate (EPA-But), are positive modulators of NMDARs. Furthermore, we revealed that EPA-But has a disuse-dependent positive allosteric effect, being similar in that regard to endogenous...
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Role of the cannabinoid system in neurodegenerative processes
Akantisová, Lucia ; Novotný, Jiří (advisor) ; Búran, Peter (referee)
The endocannabinoid system (ECD) is involved in a significant number of physiological functions in the central and peripheral nervous system. The ECD consists of cannabinoid receptors (CB1 and CB2), endogenous ligands (ANA, 2-AG) and the enzymatic apparatus required for their synthesis (NAPE and DAGL) and degradation (FAAH, MAG). In the human brain, the cannabinoid receptor CB1 is the most widespread of the group of receptors that bind to G proteins. The signaling mechanisms of these proteins contribute to the overall homeostasis of the organism. With their activity, they affect the concentrations of second messengers, the activity of ion channels, the release of neurotransmitters, and regulate immune responses. In this context, studies in the last 20 years have focused on research in the field of neurodegenerative diseases. Today, i tis known that treatment with cannabinoid compounds improves neurological deficits associated with neuronal damage and alleviates inflammatory processes in animal models of Alzheimer's disease, Parkinson's disease and multiple sclerosis. At the clinical level, treatment with cannabinoids has helped with certain accompanying symptoms occuring in neurodegenerative diseases such as neuropathic pain, insomnia and spasticity. Key words: endocannabinoid system, cannabinoids,...
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Pharmacotherapy in the treatment of opioid addiction
Bodinková, Jolana ; Novotný, Jiří (advisor) ; Kašík, Petr (referee)
Opiate addiction represents a difficult problem, both medically and socially. With millions of affected people, either by such kinds of addiction or its side effects, across the globe, the condition requires its resolution to be effective, which can be provided by opioid pharmacotherapy, either methadone-, buprenorphine- or naloxone-based. In regard to increasing numbers of not only cases but also deaths, related to drug overdose, opiate addiction treatments still remain underused in medical settings. This thesis summarizes pharmacotherapy practices used during opioid use disorder treatments. Its main part predominantly focuses on the description of therapeutical procedures, their advantages, and deficiencies. Keywords: opioid abuse, pharmacotherapy, methadone, buprenorphine, naloxone
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Projekce plánu společných zařízení v komplexní pozemkové úpravě ve zvolené lokalitě
NOVOTNÝ, Jiří
The master's thesis focuses on the designing of the plan of common facilities in the complex land consolidation in the selected area. The theoretical part includes a research that defines the land treatments, the extent of survey works essential for the elaboration of the plan of common facilities and further, the description of the plan of common facilities itself. Practical part proposes appropriate anti-erosive measures that should protect the agricultural soil resources in the cadastral area Rájov. The designed mea-sures help to decrease the undesirable effects of water erosion and improve the conditi-ons of the nature and landscape in the area. The results of the suggested measures are elaborated in both textual and graphic form.
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