The molecular mechanisms linking obstructive sleep apnea syndrome (OSA) to obesity and the development of metabolic diseases are still poorly understood. The role of hypoxia (a characteristic feature of OSA) in excessive fat accumulation has been proposed. The present study investigated the possible effects of hypoxia (4% oxygen) on de novo lipogenesis by tracking the major carbon sources in differentiating 3T3-L1 adipocytes. Gas-permeable cultuware was employed to cultivate 3T3-L1 adipocytes in hypoxia (4%) for 7 or 14 days of differentiation. We investigated the contribution of glutamine, glucose or acetate using 13C or 14C labelled carbons to the newly synthesized lipid pool, changes in intracellular lipid content after inhibiting citrate- or acetate-dependent pathways and gene expression of involved key enzymes. The results demonstrate that, in differentiating adipocytes, hypoxia decreased the synthesis of lipids from glucose (44.1 ± 8.8 to 27.5 ± 3.0 pmol/mg of protein, p < 0.01) and partially decreased the contribution of glutamine metabolized through the reverse tricarboxylic acid cycle (4.6% ± 0.2-4.2% ± 0.1%, p < 0.01). Conversely, the contribution of acetate, a citrate- and mitochondria-independent source of carbons, increased upon hypoxia (356.5 ± 71.4 to 649.8 ± 117.5 pmol/mg of protein, p < 0.01). Further, inhibiting the citrate- or acetate-dependent pathways decreased the intracellular lipid content by 58% and 73%, respectively (p < 0.01) showing the importance of de novo lipogenesis in hypoxia-exposed adipocytes. Altogether, hypoxia modified the utilization of carbon sources, leading to alterations in de novo lipogenesis in differentiating adipocytes and increased intracellular lipid content.
- MeSH
- acetáty * metabolismus farmakologie MeSH
- buněčná diferenciace * účinky léků MeSH
- buňky 3T3-L1 * MeSH
- citrátový cyklus MeSH
- glukosa * metabolismus MeSH
- glutamin * metabolismus MeSH
- hypoxie buňky MeSH
- lipidy biosyntéza MeSH
- lipogeneze * účinky léků MeSH
- metabolismus lipidů účinky léků MeSH
- myši MeSH
- tukové buňky * metabolismus účinky léků MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Reaktivace cytomegaloviru (CMV) po alogenní transplantaci krvetvorných buněk s její následnou antivirotickou léčbou je významnou komplikací vedoucí ke zvýšené morbiditě a mortalitě těchto pacientů. V rámci prevence rozvoje CMV nemoci byl dosud nejrozšířenější preemptivní přístup spočívající ve frekventní monitoraci CMV virémie s časným zahájením preemptivní antivirotické léčby v případě známek CMV reaktivace. Tento přístup na jedné straně vede k nízké incidenci CMV nemoci, na druhé straně však procento CMV reaktivací s nutností nasazení preemptivní léčby zůstává vysoké, přičemž již samotná reaktivace vede ke zvýšení morbidity a nerelapsové mortality. Letermovir představuje nové virostatikum s účinkem na cytomegalovirus, které má schválení SÚKL (Státního ústavu pro kontrolu léčiv) u CMV séropozitivních pacientů po alogenní transplantaci krvetvorných buněk. V registrační, randomizované, placebem kontrolované studii, jež vyústila v uvedení letermoviru do klinické praxe, byl prokázán pozitivní vliv na snížení incidence klinicky signifikantní CMV infekce a zároveň pokles nerelapsové mortality ve srovnání s placebem, především u pacientů v nejvyšším riziku CMV onemocnění. Ačkoli je letermovir v primární profylaxi CMV po alogenní transplantaci krvetvorby již běžné užíván, s jeho použitím se pojí řada nevyjasněných otázek, jako jsou optimální délka trvání profylaxe nebo jeho použití v sekundární profylaxi či preemptivní léčbě CMV reaktivace. Následující práce shrnuje v současnosti dostupná literární data týkající se použití letermoviru u pacientů po alogenní transplantaci krvetvorných buněk.
Cytomegalovirus (CMV) reactivation after allogeneic haematopoietic stem cell transplantation and its subsequent antiviral treatment is a significant complication leading to increased morbidity and mortality in these patients. Frequent monitoring of CMV viremia with early pre-emptive antiviral treatment in case of CMV reactivation represents the most widely used option to date for preventing CMV disease. While this approach leads to a low incidence of CMV disease, the percentage of CMV reactivations requiring pre-emptive therapy remains high and increased morbidity and non-relapse mortality are thus associated with CMV reactivation per se. Letermovir is a new antiviral drug with anti-CMV activity approved for use in CMV seropositive patients after allogeneic hematopoietic stem cell transplantation. A randomized, placebo-controlled study that led to the introduction of letermovir into clinical practice demonstrated a positive effect in reducing the incidence of clinically significant CMV infection as well as non-relapse mortality compared to placebo, especially in patients at high risk of CMV disease. Although it is already commonly used in primary CMV prophylaxis after allogeneic hematopoietic transplantation, its use is associated with certain unresolved issues such as the optimal duration of prophylaxis or its use in secondary prophylaxis or pre-emptive treatment of CMV reactivation. The following article summarizes currently available data on the use of letermovir in patients after allogeneic hematopoietic stem cell transplantation.
- Klíčová slova
- letermovir,
- MeSH
- acetáty farmakologie terapeutické užití MeSH
- cytomegalovirové infekce * prevence a kontrola MeSH
- homologní transplantace MeSH
- klinické zkoušky jako téma MeSH
- léková rezistence MeSH
- lidé MeSH
- preexpoziční profylaxe MeSH
- rizikové faktory MeSH
- transplantace kostní dřeně * MeSH
- Check Tag
- lidé MeSH
Bark beetles kill apparently vigorous conifers during epidemics by means of pheromone-mediated aggregation. During non-endemic conditions the beetles are limited to use trees with poor defense, like wind-thrown. To find olfactory cues that help beetles to distinguish between trees with strong or weak defense, we collected volatiles from the bark surface of healthy felled or standing Picea abies trees. Furthermore, living trees were treated with methyl jasmonate in order to induce defense responses. Volatiles were analyzed by combined gas chromatography and electroantennographic detection (GC-EAD) on Ips typographus antennae. Compounds eliciting antennal responses were characterized by single sensillum recording for identification of specific olfactory sensory neurons (OSN). Release of monoterpene hydrocarbons decreased, while oxygenated compounds increased, from spring to early summer in felled trees. In both beetle sexes particular strong EAD activity was elicited by trace amounts of terpene alcohols and ketones. 4-Thujanol gave a very strong response and the absolute configuration of the tested natural product was assigned to be (+)-trans-(1R,4S,5S)-thujanol by stereoselective synthesis and enantioselective gas chromatography. One type of OSN responded to all ketones and five other OSN were characterized by the type of compounds that elicited responses. Three new OSN classes were found. Of the eight EAD-active compounds found in methyl jasmonate-treated bark, the known anti-attractant 1,8-cineole was the one most strongly induced. Our data support the hypothesis that highly active oxygenated host volatiles could serve as positive or negative cues for host selection in I. typographus and in other bark beetles.
- MeSH
- acetáty farmakologie MeSH
- brouci fyziologie MeSH
- cyklopentany farmakologie MeSH
- elektrofyziologické jevy účinky léků MeSH
- kůra rostlin chemie účinky léků metabolismus MeSH
- monoterpeny chemická syntéza chemie farmakologie MeSH
- oxylipiny farmakologie MeSH
- plynová chromatografie s hmotnostně spektrometrickou detekcí MeSH
- smrk chemie metabolismus MeSH
- stereoizomerie MeSH
- styren chemie farmakologie MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- MeSH
- acetáty farmakologie škodlivé účinky terapeutické užití MeSH
- hormon uvolňující gonadotropiny agonisté MeSH
- leiomyom * farmakoterapie MeSH
- lidé MeSH
- nemoci jater etiologie prevence a kontrola MeSH
- progesteron agonisté MeSH
- receptory progesteronu terapeutické užití MeSH
- výsledek terapie MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
Indoxyl sulfate has been identified as a major factor in the dysregulation of several genes. It is classified as a poorly dialyzable uremic toxin and thus a leading cause in the poor survival rate of dialysis patients. A monocentric, prospective, open cohort study was performed in 43 male patients undergoing chronic renal replacement therapy in a single hemodialysis center. The aim of the study was to determine the influence of acetate- versus citrate-buffered dialysis fluids in hemodialysis (HD) and postdilution hemodiafiltration (HDF) settings on the elimination of indoxyl sulfate. Also, additional factors potentially influencing the serum concentration of indoxyl sulfate were evaluated. For this purpose, the predialysis and postdialysis concentration ratio of indoxyl sulfate and total protein was determined. The difference was of 1.15 (0.61; 2.10), 0.89 (0.53; 1.66), 0.32 (0.07; 0.63), and 0.44 (0.27; 0.77) μmol/g in acetate HD and HDF and citrate HD and HDF, respectively. Acetate HD and HDF were superior when concerning IS elimination when compared to citrate HD and HDF. Moreover, residual diuresis was determined as the only predictor of lower indoxyl sulfate concentration, suggesting that it should be preserved as long as possible. This trial is registered with EU PAS Register of Studies EUPAS23714.
- MeSH
- acetáty farmakologie MeSH
- dialýza ledvin metody MeSH
- dialyzační roztoky chemie farmakologie MeSH
- hemodiafiltrace metody MeSH
- hydrogenuhličitany MeSH
- indican krev farmakokinetika MeSH
- kyselina citronová krev farmakologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- nemoci ledvin terapie MeSH
- prospektivní studie MeSH
- senioři MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky MeSH
Plant defense metabolites are well known to be regulated developmentally. The optimal defense (OD) theory posits that a tssue's fitness values and probability of attack should determine defense metabolite allocations. Young leaves are expected to provide a larger fitness value to the plant, and therefore their defense allocations should be higher when compared with older leaves. The mechanisms that coordinate development with defense remain unknown and frequently confound tests of the OD theory predictions. Here we demonstrate that cytokinins (CKs) modulate ontogeny-dependent defenses in Nicotiana attenuata. We found that leaf CK levels highly correlate with inducible defense expressions with high levels in young and low levels in older leaves. We genetically manipulated the developmental patterns of two different CK classes by using senescence- and chemically inducible expression of CK biosynthesis genes. Genetically modifying the levels of different CKs in leaves was sufficient to alter ontogenic patterns of defense metabolites. We conclude that the developmental regulation of growth hormones that include CKs plays central roles in connecting development with defense and therefore in establishing optimal patterns of defense allocation in plants.
- MeSH
- acetáty metabolismus farmakologie MeSH
- býložravci fyziologie MeSH
- časové faktory MeSH
- cyklopentany metabolismus farmakologie MeSH
- cytokininy metabolismus MeSH
- geneticky modifikované rostliny MeSH
- interakce hostitele a parazita účinky léků MeSH
- listy rostlin genetika metabolismus parazitologie MeSH
- Manduca fyziologie MeSH
- nemoci rostlin genetika parazitologie MeSH
- oxylipiny metabolismus farmakologie MeSH
- regulace genové exprese u rostlin účinky léků MeSH
- regulátory růstu rostlin metabolismus farmakologie MeSH
- rostlinné proteiny genetika metabolismus MeSH
- tabák genetika metabolismus parazitologie MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
The molecular and cellular mechanisms of enhanced toxic effects in tumor cells of the Pt(IV) derivatives of antitumor oxaliplatin containing axial dichloroacetate (DCA) ligands were investigated. DCA ligands were chosen because DCA has shown great potential as an apoptosis sensitizer and anticancer agent reverting the Wartburg effect. In addition, DCA reverses mitochondrial changes in a wide range of cancers, promoting tumor cell apoptosis in a mitochondrial-dependent pathway. We demonstrate that (i) the transformation of oxaliplatin to its Pt(IV) derivatives containing axial DCA ligands markedly enhances toxicity in cancer cells and helps overcome inherent and acquired resistance to cisplatin and oxaliplatin; (ii) a significant fraction of the intact molecules of DCA conjugates with Pt(IV) derivative of oxaliplatin accumulates in cancer cells where it releases free DCA; (iii) mechanism of biological action of the Pt(IV) derivatives of oxaliplatin containing DCA ligands is connected with the effects of DCA released in cancer cells from the Pt(IV) prodrugs on mitochondria and metabolism of glucose; (iv) treatments with the Pt(IV) derivatives of oxaliplatin containing DCA ligands activate an autophagic response in human colorectal cancer cells; (v) the toxic effects in cancer cells of the Pt(IV) derivatives of oxaliplatin containing DCA ligands can be potentiated if cells are treated with these prodrugs in combination with 5-fluorouracil. These properties of the Pt(IV) derivatives of oxaliplatin containing DCA ligands provide opportunities for further development of new platinum-based agents with the capability of killing cancer cells resistant to conventional antitumor platinum drugs used in the clinic.
- Klíčová slova
- FEXOFENADIN, MONTELUKAST,
- MeSH
- acetáty farmakologie terapeutické užití MeSH
- angioedém diagnóza MeSH
- chinoliny farmakologie terapeutické užití MeSH
- cystitida diagnóza MeSH
- diferenciální diagnóza MeSH
- hydroxychlorochin farmakologie terapeutické užití MeSH
- imunologické testy MeSH
- klinické laboratorní techniky MeSH
- lidé středního věku MeSH
- lidé MeSH
- sinusitida diagnóza MeSH
- systémový lupus erythematodes * diagnóza farmakoterapie MeSH
- terfenadin analogy a deriváty farmakologie terapeutické užití MeSH
- výsledek terapie MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
Ellman's method is a standard protocol for the determination of cholinesterases activity. Though the method is ready for laboratory purposes, it has some drawbacks as well. In the current article, 2,6-dichloroindophenol acetate is performed as a chromogenic substrate suitable for acetylcholinesterase (AChE) activity examination. Michaelis constant and maximal velocity for 2,6-dichloroindophenol acetate were determined (38.0 µM and 244 pkat) and compared to the values for acetythiocholine (K(m) 0.18 mM; V(max) 5.1 nkat). Docking for 2,6-dichloroindophenol acetate and human AChE was done as well. In conclusion, 2,6-dichloroindophenol acetate seems to be suitable chromogenic substrate for AChE and spectrophotometry and based on this it can be easily performed whenever AChE activity should be tested.
- MeSH
- 2,6-dichlorindofenol chemická syntéza chemie farmakologie MeSH
- acetáty chemická syntéza chemie farmakologie MeSH
- acetylcholinesterasa metabolismus MeSH
- cholinesterasové inhibitory chemická syntéza chemie farmakologie MeSH
- lidé MeSH
- molekulární struktura MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
