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Expression of cytokines, particularly chemokines, after application of acyclic nucleoside phosphonates
Potměšil, Petr ; Zídek, Zdeněk (advisor) ; Otová, Berta (referee) ; Farghali, Hassan (referee)
Acyclic nucleoside phosphonates (ANPs) are novel class of virostatics, that inhibit replication of both DNA viruses and retroviruses. ANP approved for the treatment of viral diseases are: tenofovir (Viread®) for the therapy of AIDS, adefovir (Hepsera®) for the treatment of hepatitis B and cidofovir (Vistide®), that is used in HIV-1 positive patients suffering from retinitis caused by cytomegalovirus [23, 24]. Some ANPs, such as tenofovir, are endowed by immunomodulatory properties that can non specifically influence replication of viruses. Tenofovir has been shown previously to increase gene expression of nitric oxide, cytokines TNF- , IL-10 and chemokines RANTES, MIP-1 [6, 22, 30]. In present experiments we investigated possible immunobiological properties of newly synthesized derivatives of ANPs in vitro using mouse macrophages and lymphocytes (or human leukocytes, respectively). N6-substituted derivatives of adenine or 2,6-diaminopurine, that possess phosphonomethoxyethyl or phosphonomethoxypropyl moiety at the position N9 of the heterocyclic base were included in the study. Some of these compounds were found to activate production of nitric oxide, cytokines TNF- , IL-10 and chemokines RANTES, MIP- 1 [21]. Various hydroxylated derivatives of ANPs were also screened for their immunobiological potential....
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Pharmacological modifications of potential signal systems regulating metabolism of adipocytes and hepatocytes and their influence on obesity
Hodis, Jiří ; Farghali, Hassan (advisor) ; Kršiak, Miloslav (referee) ; Otová, Berta (referee)
v anglickém jazyce: Thesis abstract: Background and aims: Both obesity and metabolic syndrome form severe health problems in the whole world. Nevertheless the armament of pharmacotherapy for both diseases remains unsatisfactory. We aimed our work to main organs in risk of the mentioned diseases -liver and visceral fat using hepatocytes and visceral adipocytes as model. We detected 3 main metabolic and signalization activities- glycogenolysis, Nitric oxide (NO) production and transcription of inducible NO synthase (iNOS) in hepatocytes, lipolysis, NO production and iNOS transcription rate in adipocytes. We directed our interest to combination of peroxisome proliferation activator receptor γ (PPARγ) agonist, antagonist and β3 adrenergic agonist in the culture of epididymal rat adipocytes in the first part of our work. While in the second part we investigated the influence of β and α adrenergic mimetics, adrenergic blockers in the culture of rat high glycogen content hepatocytes. Methods: NO production was detected under the active agents treatments by detection of NO oxidative products NO2 and NO3 in media. Glycogenolysis was measured as free glucose rise released by hepatocytes into the media. NOS transcription level was extrapolated after comparative polymerase chain reaction with reverse...
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Orphan Nuclear Receptor TLX (NR2E1) in Regulation of Cell Reproduction and Differentiation
Raška, Otakar ; Kostrouch, Zdeněk (advisor) ; Otová, Berta (referee) ; Nedvídková, Jara (referee)
Nuclear receptors constitute a large family of transcription factors that are powerful regulators of animal tissue metabolism, homeostasis, tissue maintenance and development. They are particularly attractive for their ability to respond to the binding of hormones, metabolites, xenobiotics and artificially prepared molecules and transmit the interaction with these small lipophylic molecules to specific regulatory potential. In search for nuclear receptors that are likely to be critical for neural tissues in invertebrates and conserved during the evolution of animals, we have identified a close homologue of vertebrate TLX in a planarian Schmidtea mediterranea. Planaria represent very promising biological model systems for studies on tissue maintenance and regeneration. Planaria are able to resorb their tissues and use them as sources of energy during fasting and they re-build their bodies from neoblasts when food is plentiful. Our search in Schmidtea mediterranea's publicly accessible genome sequencing data indicated that planarian genome contains at least one gene with a high degree of similarity to vertebrate TLX. We cloned full length CDS (coding DNA sequence of cDNA) and characterized the gene functionally. This showed that the planarian and vertebrate NR2E1 are highly similar...
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Genetic basis of selected chronic nephropathies
Šafránková, Hana ; Merta, Miroslav (advisor) ; Otová, Berta (referee) ; Teplan, Vladimír (referee)
Keywords: nephrotic syndrome, FSGS, MCD, podocin, NPHS2, VEGF polymorphisms Nephrotic syndrome (NS), caused by minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) has about 20% of the genetic background caused by mutations in the NPHS2 gene encoding protein podocin that plays an important role in the kidney filtration barrier. The aim of this work is to introduce mutation analysis of the NPHS2 gene and to examine the sample of Czech patients with NS. We examined 71 patients with FSGS/MCD and subsequently, on the basis of these data we tested two common polymorphisms in NPHS2 (p.R229Q and p.P20L) in the group of patients with different glomerulonephritides (GN): IgA nephropathy (IGAN) (n = 169), membranous GN (MGN) (n = 46) and control group (n = 300). We also examined two polymorphisms located in the promoter of vascular endothelial growth factor (VEGF) (-2578 A/C, -1154 A/G) and influencing the level of its expression. VEGF is produced by specialized kidney cells called podocytes and has a function in the formation of blood vessels and capillary fenestration. The sample included 56 patients (pts) with FSGS/MCD, 113 pts with IGAN, 44 pts with MGN and 311 controls. No mutation in NPHS2 gene was found in patients with FSGS/MCD arising in adulthood. We detected one homozygous...
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Orphan Nuclear Receptor TLX (NR2E1) in Regulation of Cell Reproduction and Differentiation
Raška, Otakar ; Kostrouch, Zdeněk (advisor) ; Otová, Berta (referee) ; Nedvídková, Jara (referee)
Nuclear receptors constitute a large family of transcription factors that are powerful regulators of animal tissue metabolism, homeostasis, tissue maintenance and development. They are particularly attractive for their ability to respond to the binding of hormones, metabolites, xenobiotics and artificially prepared molecules and transmit the interaction with these small lipophylic molecules to specific regulatory potential. In search for nuclear receptors that are likely to be critical for neural tissues in invertebrates and conserved during the evolution of animals, we have identified a close homologue of vertebrate TLX in a planarian Schmidtea mediterranea. Planaria represent very promising biological model systems for studies on tissue maintenance and regeneration. Planaria are able to resorb their tissues and use them as sources of energy during fasting and they re-build their bodies from neoblasts when food is plentiful. Our search in Schmidtea mediterranea's publicly accessible genome sequencing data indicated that planarian genome contains at least one gene with a high degree of similarity to vertebrate TLX. We cloned full length CDS (coding DNA sequence of cDNA) and characterized the gene functionally. This showed that the planarian and vertebrate NR2E1 are highly similar...
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Pharmacological modifications of potential signal systems regulating metabolism of adipocytes and hepatocytes and their influence on obesity
Hodis, Jiří ; Farghali, Hassan (advisor) ; Kršiak, Miloslav (referee) ; Otová, Berta (referee)
v anglickém jazyce: Thesis abstract: Background and aims: Both obesity and metabolic syndrome form severe health problems in the whole world. Nevertheless the armament of pharmacotherapy for both diseases remains unsatisfactory. We aimed our work to main organs in risk of the mentioned diseases -liver and visceral fat using hepatocytes and visceral adipocytes as model. We detected 3 main metabolic and signalization activities- glycogenolysis, Nitric oxide (NO) production and transcription of inducible NO synthase (iNOS) in hepatocytes, lipolysis, NO production and iNOS transcription rate in adipocytes. We directed our interest to combination of peroxisome proliferation activator receptor γ (PPARγ) agonist, antagonist and β3 adrenergic agonist in the culture of epididymal rat adipocytes in the first part of our work. While in the second part we investigated the influence of β and α adrenergic mimetics, adrenergic blockers in the culture of rat high glycogen content hepatocytes. Methods: NO production was detected under the active agents treatments by detection of NO oxidative products NO2 and NO3 in media. Glycogenolysis was measured as free glucose rise released by hepatocytes into the media. NOS transcription level was extrapolated after comparative polymerase chain reaction with reverse...
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Expression of cytokines, particularly chemokines, after application of acyclic nucleoside phosphonates
Potměšil, Petr ; Zídek, Zdeněk (advisor) ; Otová, Berta (referee) ; Farghali, Hassan (referee)
Acyclic nucleoside phosphonates (ANPs) are novel class of virostatics, that inhibit replication of both DNA viruses and retroviruses. ANP approved for the treatment of viral diseases are: tenofovir (Viread®) for the therapy of AIDS, adefovir (Hepsera®) for the treatment of hepatitis B and cidofovir (Vistide®), that is used in HIV-1 positive patients suffering from retinitis caused by cytomegalovirus [23, 24]. Some ANPs, such as tenofovir, are endowed by immunomodulatory properties that can non specifically influence replication of viruses. Tenofovir has been shown previously to increase gene expression of nitric oxide, cytokines TNF- , IL-10 and chemokines RANTES, MIP-1 [6, 22, 30]. In present experiments we investigated possible immunobiological properties of newly synthesized derivatives of ANPs in vitro using mouse macrophages and lymphocytes (or human leukocytes, respectively). N6-substituted derivatives of adenine or 2,6-diaminopurine, that possess phosphonomethoxyethyl or phosphonomethoxypropyl moiety at the position N9 of the heterocyclic base were included in the study. Some of these compounds were found to activate production of nitric oxide, cytokines TNF- , IL-10 and chemokines RANTES, MIP- 1 [21]. Various hydroxylated derivatives of ANPs were also screened for their immunobiological potential....
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