(1) Objectives: Intestinal failure in home parenteral nutrition patients (HPNPs) results in oxidative stress and liver damage. This study investigated how a high dose of fish oil (FO) added to various lipid emulsions influences antioxidant status and liver function markers in HPNPs. (2) Methods: Twelve HPNPs receiving Smoflipid for at least 3 months were given FO (Omegaven) for a further 4 weeks. Then, the patients were randomized to subsequently receive Lipoplus and ClinOleic for 6 weeks or vice versa plus 4 weeks of Omegaven after each cycle in a crossover design. Twelve age- and sex-matched healthy controls (HCs) were included. (3) Results: Superoxide dismutase (SOD1) activity and oxidized-low-density lipoprotein concentration were higher in all baseline HPN regimens compared to HCs. The Omegaven lowered SOD1 compared to baseline regimens and thus normalized it toward HCs. Lower paraoxonase 1 activity and fibroblast growth factor 19 (FGF19) concentration and, on the converse, higher alkaline phosphatase activity and cholesten concentration were observed in all baseline regimens compared to HCs. A close correlation was observed between FGF19 and SOD1 in baseline regimens. (4) Conclusions: An escalated dose of FO normalized SOD1 activity in HPNPs toward that of HCs. Bile acid metabolism was altered in HPNPs without signs of significant cholestasis and not affected by Omegaven.
The platinum(II) complex [Pt(1S,2S-diaminocyclohexane)(5,6-dimethyl-1,10-phenanthroline)]2+ (PtII56MeSS, 1) exhibits high potency across numerous cancer cell lines acting by a multimodal mechanism. However, 1 also displays side toxicity and in vivo activity; all details of its mechanism of action are not entirely clear. Here, we describe the synthesis and biological properties of new platinum(IV) prodrugs that combine 1 with one or two axially coordinated molecules of diclofenac (DCF), a non-steroidal anti-inflammatory cancer-selective drug. The results suggest that these Pt(IV) complexes exhibit mechanisms of action typical for Pt(II) complex 1 and DCF, simultaneously. The presence of DCF ligand(s) in the Pt(IV) complexes promotes the antiproliferative activity and selectivity of 1 by inhibiting lactate transporters, resulting in blockage of the glycolytic process and impairment of mitochondrial potential. Additionally, the investigated Pt(IV) complexes selectively induce cell death in cancer cells, and the Pt(IV) complexes containing DCF ligands induce hallmarks of immunogenic cell death in cancer cells.
- MeSH
- antiflogistika nesteroidní farmakologie MeSH
- antitumorózní látky * MeSH
- diklofenak farmakologie MeSH
- ligandy MeSH
- nádorové buněčné linie MeSH
- nádory * MeSH
- organoplatinové sloučeniny farmakologie MeSH
- platina MeSH
- prekurzory léčiv * MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Úvod: Devítikolíkový test (NHPT – Nine Hole Peg Test), Purdue Pegboard Test (PPT) a Box and Block Test (BBT) patří mezi standardizované testy, které ergoterapeuti často používají v praxi k objektivnímu hodnocení jemné motoriky horních končetin osob s nejrůznějšími typy zdravotních problémů. Do října 2021 však nebyla k dispozici česká verze manuálů obsahujících i slovní instrukce, které jsou nezbytné pro jejich standardizované provedení. Cíl: Cílem této studie bylo zjistit, jakým způsobem byly v době šetření prováděny standardizované testy NHPT, PPT a BBT v praxi ergoterapeutů v České republice. Metody: V březnu a dubnu 2021 byl elektronický dotazník rozšířen mezi české ergoterapeuty. Vyplnilo ho celkem 121 respondentů, 34 odpovědí však bylo vyloučeno kvůli nesplnění kritérií. Výsledky: Na základě analýzy odpovědí od 87 českých ergoterapeutů bylo potvrzeno, že se ergoterapeuti v ČR mezi sebou významně lišili ve způsobech provádění NHPT, PPT i BBT, přestože se jedná o standardizované testy. Zásadním rozdílem mezi ergoterapeuty byl způsob poskytování instrukcí testovaným osobám při provádění zmíněných standardizovaných testů. Bylo zjištěno, že někteří ergoterapeuti říkali testovaným osobám instrukce vlastními slovy navzdory pravidlům používání těchto testů, jiní opomíjeli předvádění názorné ukázky požadovaného úkolu. Více ergoterapeutů se shodlo, že na pracovišti neměli možnost nahlédnout do manuálů nebo nečetli manuál vůbec, jiní uváděli skutečnost, že měli na pracovištích k dispozici různé verze manuálů v češtině a angličtině. Příčinou odlišného způsobu provádění NHPT, PPT a BBT mohla být zejména tehdejší nedostupnost jejich manuálů v češtině. Shrnutí: Od října 2021 mají ergoterapeuti z ČR volně k dispozici kvalitně vypracované české rozšířené verze manuálů pro NHPT, PPT i BBT. Mohou tak konečně zcela jednotně provádět standardizované hodnocení jemné motoriky horních končetin i v rámci výzkumných studií a být velmi přínosnými členy výzkumných týmů.
Introduction: The Nine Hole Peg Test (NHPT), Purdue Pegboard Test (PPT) and Box and Block Test (BBT) represent the standardized tests that occupational therapists often use in practice to objectively assess upper limb fine motor skills of people with various types of health conditions. However, until October 2021, a Czech version of the manuals containing the verbal instructions necessary for the standardized procedure was not available for occupational therapists. Aim: The aim of this study was to find out how standardized NHPT, PPT and BBT tests were performed by occupational therapists in the Czech Republic at the time of the survey. Methods: Therefore, in March and April 2021, an electronic questionnaire was spread among Czech occupational therapists. It was completed by a total of 121 respondents, but 34 responses were excluded for not meeting the inclusion criteria. Results: Based on the analysis of responses from 87 Czech occupational therapists, it was confirmed that occupational therapists in the Czech Republic differed significantly in the way of performing NHPT, PPT and BBT, although these are standardized tests. The main differences between the occupational therapists were in the way of giving instructions to the tested persons to perform the mentioned standardized tests. It was found that some occupational therapists, despite the rules for using these tests, gave the tested persons instructions in their own words, while others neglected to demonstrate the required task. Several occupational therapists agreed that they did not have the opportunity to look at the manuals at the workplace, or did not read the manual at all, others stated that they had different versions of the manuals available in the Czech and English at the workplace. The reason for the different way of performing NHPT, PPT and BBT could be mainly the unavailability of the manuals in the Czech language. Conclusion: Since October 2021, occupational therapists from the Czech Republic have well-edited Czech extended versions of the manuals for NHPT, PPT and BBT available for free. Finally, they can perform standardized assessments of upper limbs fine motor skills even in research studies and be very beneficial members of research teams.
- Klíčová slova
- standardizovaný test,
- MeSH
- ergoterapie MeSH
- lidé MeSH
- motorické dovednosti * MeSH
- průzkumy a dotazníky MeSH
- Check Tag
- lidé MeSH
The infarct size-limiting effect elicited by cold acclimation (CA) is accompanied by increased mitochondrial resistance and unaltered β1-adrenergic receptor (AR) signaling persisting for 2 wk at room temperature. As the mechanism of CA-elicited cardioprotection is not fully understood, we examined the role of the salvage β2-AR/Gi/Akt pathway. Male Wistar rats were exposed to CA (8°C, 5 wk), whereas the recovery group (CAR) was kept at 24°C for additional 2 wk. We show that the total number of myocardial β-ARs in the left ventricular myocardium did not change after CA but decreased after CAR. We confirmed the infarct size-limiting effect in both CA and CAR groups. Acute administration of β2-AR inhibitor ICI-118551 abolished the protective effect in the CAR group but had no effect in the control and CA groups. The inhibitory Giα1/2 and Giα3 proteins increased in the membrane fraction of the CAR group, and the phospho-Akt (Ser473)-to-Akt ratio also increased. Expression, phosphorylation, and mitochondrial location of the Akt target glycogen synthase kinase (GSK-3β) were affected neither by CA nor by CAR. However, GSK-3β translocated from the Z-disk to the H-zone after CA, and acquired its original location after CAR. Our data indicate that the cardioprotection observed after CAR is mediated by the β2-AR/Gi pathway and Akt activation. Further studies are needed to unravel downstream targets of the central regulators of the CA process and the downstream targets of the Akt protein after CAR.NEW & NOTEWORTHY Cardioprotective effect of cold acclimation and that persisting for 2 wk after recovery engage in different mechanisms. The β2-adrenoceptor/Gi pathway and Akt are involved only in the mechanism of infarct size-limiting effect occurring during the recovery phase. GSK-3β translocated from the Z-line to the H-zone of sarcomeres by cold acclimation returns back to the original position after the recovery phase. The results provide new insights potentially useful for the development of cardiac therapies.
- MeSH
- aklimatizace MeSH
- beta-2-adrenergní receptory MeSH
- fosforylace MeSH
- GSK3B MeSH
- krysa rodu rattus MeSH
- potkani Wistar MeSH
- protoonkogenní proteiny c-akt metabolismus MeSH
- reperfuzní poškození myokardu * MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
DNA-dependent DNA and RNA polymerases are important modulators of biological functions such as replication, transcription, recombination, or repair. In this work performed in cell-free media, we studied the ability of selected DNA polymerases to overcome a monofunctional adduct of the cytotoxic/antitumor platinum-acridinylthiourea conjugate [PtCl(en)(L)](NO3)2 (en = ethane-1,2-diamine, L = 1-[2-(acridin-9-ylamino)ethyl]-1,3-dimethylthiourea) (ACR) in its favored 5'-CG sequence. We focused on how a single site-specific ACR adduct with intercalation potency affects the processivity and fidelity of DNA-dependent DNA polymerases involved in translesion synthesis (TLS) and repair. The ability of the G(N7) hybrid ACR adduct formed in the 5'-TCGT sequence of a 24-mer DNA template to inhibit the synthesis of a complementary DNA strand by the exonuclease-deficient Klenow fragment of DNA polymerase I (KFexo-) and human polymerases eta, kappa, and iota was supplemented by thermodynamic analysis of the polymerization process. Thermodynamic parameters of a simulated translesion synthesis across the ACR adduct were obtained by using microscale thermophoresis (MST). Our results show a strong inhibitory effect of an ACR adduct on enzymatic TLS: there was only small synthesis of a full-length product (less than 10%) except polymerase eta (~20%). Polymerase eta was able to most efficiently bypass the ACR hybrid adduct. Incorporation of a correct dCMP opposite the modified G residue is preferred by all the four polymerases tested. On the other hand, the frequency of misinsertions increased. The relative efficiency of misinsertions is higher than that of matched cytidine monophosphate but still lower than for the nonmodified control duplex. Thermodynamic inspection of the simulated TLS revealed a significant stabilization of successively extended primer/template duplexes containing an ACR adduct. Moreover, no significant decrease of dissociation enthalpy change behind the position of the modification can contribute to the enzymatic TLS observed with the DNA-dependent, repair-involved polymerases. This TLS could lead to a higher tolerance of cancer cells to the ACR conjugate compared to its enhanced analog, where thiourea is replaced by an amidine group: [PtCl(en)(L)](NO3)2 (complex AMD, en = ethane-1,2-diamine, L = N-[2-(acridin-9-ylamino)ethyl]-N-methylpropionamidine).
- MeSH
- adukty DNA chemie MeSH
- DNA-dependentní DNA-polymerasy metabolismus MeSH
- interkalátory chemie MeSH
- lidé MeSH
- močovina analogy a deriváty chemie MeSH
- oprava DNA * MeSH
- organoplatinové sloučeniny chemie MeSH
- poškození DNA * MeSH
- replikace DNA MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Translesion synthesis (TLS) through DNA adducts of antitumor platinum complexes has been an interesting aspect of DNA synthesis in cells treated with these metal-based drugs because of its correlation to drug sensitivity. We utilized model systems employing a DNA lesion derived from a site-specific monofunctional adduct formed by antitumor [PtCl(en)(L)](NO3)2 (complex AMD, en = ethane-1,2-diamine, L = N-[2-(acridin-9-ylamino)ethyl]-N-methylpropionamidine) at a unique G residue. The catalytic efficiency of TLS DNA polymerases, which differ in their processivity and fidelity for the insertion of correct dCTP, with respect to the other incorrect nucleotides, opposite the adduct of AMD, was investigated. For a deeper understanding of the factors that control the bypass of the site-specific adducts of AMD catalyzed by DNA polymerases, we also used microscale thermophoresis (MST) to measure the thermodynamic changes associated with TLS across a single, site-specific adduct formed in DNA by AMD. The relative catalytic efficiency of the investigated DNA polymerases for the insertion of correct dCTP, with respect to the other incorrect nucleotides, opposite the AMD adduct, was reduced. Nevertheless, incorporation of the correct C opposite the G modified by AMD of the template strand was promoted by an increasing thermodynamic stability of the resulting duplex. The reduced relative efficiency of the investigated DNA polymerases may be a consequence of the DNA intercalation of the acridine moiety of AMD and the size of the adduct. The products of the bypass of this monofunctional lesion produced by AMD and DNA polymerases also resulted from the misincorporation of dNTPs opposite the platinated G residues. The MST analysis suggested that thermodynamic factors may contribute to the forces that governed enhanced incorporation of the incorrect dNTPs by DNA polymerases.
- MeSH
- adukty DNA chemie genetika metabolismus MeSH
- akridiny chemie farmakologie MeSH
- biokatalýza MeSH
- DNA-dependentní DNA-polymerasy metabolismus MeSH
- DNA biosyntéza MeSH
- guanin metabolismus MeSH
- katalýza MeSH
- nukleotidy genetika metabolismus MeSH
- oprava DNA MeSH
- replikace DNA MeSH
- sloučeniny platiny chemie farmakologie MeSH
- tepelná difuze MeSH
- termodynamika MeSH
- Publikační typ
- časopisecké články MeSH
The search for more effective platinum anticancer drugs has led to the design, synthesis, and preclinical testing of hundreds of new platinum complexes. This search resulted in the recognition and subsequent FDA approval of the third-generation Pt(II) anticancer drug, [Pt(1,2-diaminocyclohexane)(oxalate)], oxaliplatin, as an effective agent in treating colorectal and gastrointestinal cancers. Another promising example of the class of anticancer platinum(II) complexes incorporating the Pt(1,n-diaminocycloalkane) moiety is kiteplatin ([Pt(cis-1,4-DACH)Cl2], DACH = diaminocyclohexane). We report here our progress in evaluating the role of the cycloalkyl moiety in these complexes focusing on the synthesis, characterization, evaluation of the antiproliferative activity in tumor cells and studies of the mechanism of action of new [Pt(cis-1,3-diaminocycloalkane)Cl2] complexes wherein the cis-1,3-diaminocycloalkane group contains the cyclobutyl, cyclopentyl, and cyclohexyl moieties. We demonstrate that [Pt(cis-1,3-DACH)Cl2] destroys cancer cells with greater efficacy than the other two investigated 1,3-diamminocycloalkane derivatives, or cisplatin. Moreover, the investigated [Pt(cis-1,3-diaminocycloalkane)Cl2] complexes show selectivity toward tumor cells relative to non-tumorigenic normal cells. We also performed several mechanistic studies in cell-free media focused on understanding some early steps in the mechanism of antitumor activity of bifunctional platinum(II) complexes. Our data indicate that reactivities of the investigated [Pt(cis-1,3-diaminocycloalkane)Cl2] complexes and cisplatin with glutathione and DNA binding do not correlate with antiproliferative activity of these platinum(II) complexes in cancer cells. In contrast, we show that the higher antiproliferative activity in cancer cells of [Pt(cis-1,3-DACH)Cl2] originates from its highest hydrophobicity and most efficient cellular uptake.
- MeSH
- antitumorózní látky chemická syntéza farmakologie MeSH
- apoptóza účinky léků MeSH
- cisplatina farmakologie normy MeSH
- cyklické uhlovodíky chemická syntéza MeSH
- DNA chemie MeSH
- glutathion chemie MeSH
- léky antitumorózní - screeningové testy MeSH
- lidé MeSH
- nádorové buněčné linie MeSH
- organokovové sloučeniny chemická syntéza farmakologie MeSH
- permeabilita buněčné membrány MeSH
- platina chemie MeSH
- proliferace buněk účinky léků MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Omega-3 polyunsaturated fatty acids (ω-3PUFAs) are introduced into parenteral nutrition (PN) as hepatoprotective but may be susceptible to the lipid peroxidation while olive oil (OO) is declared more peroxidation resistant. We aimed to estimate how the lipid composition of PN mixture affects plasma and erythrocyte lipidome and the propensity of oxidative stress. A cross-sectional comparative study was performed in a cohort of adult patients who were long-term parenterally administered ω-3 PUFAs without (FO/-, n = 9) or with (FO/OO, n = 13) olive oil and healthy age- and sex-matched controls, (n = 30). Lipoperoxidation assessed as plasma and erythrocyte malondialdehyde content was increased in both FO/- and FO/OO groups but protein oxidative stress (protein carbonyls in plasma) and low redox status (GSH/GSSG in erythrocytes) was detected only in the FO/- subcohort. The lipidome of all subjects receiving ω-3 PUFAs was enriched with lipid species containing ω-3 PUFAs (FO/-˃FO/OO). Common characteristic of all PN-dependent patients was high content of fatty acyl-esters of hydroxy-fatty acids (FAHFAs) in plasma while acylcarnitines and ceramides were enriched in erythrocytes. Plasma and erythrocyte concentrations of plasmanyls and plasmalogens (endogenous antioxidants) were decreased in both patient groups with a significantly more pronounced effect in FO/-. We confirmed the protective effect of OO in PN mixtures containing ω-3 PUFAs.
- MeSH
- antioxidancia metabolismus MeSH
- dospělí MeSH
- erytrocyty metabolismus MeSH
- kyseliny mastné omega-3 farmakologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- lipidomika MeSH
- lipidy krev MeSH
- nemoci střev krev terapie MeSH
- olivový olej farmakologie MeSH
- oxidační stres účinky léků MeSH
- parenterální výživa škodlivé účinky metody MeSH
- průřezové studie MeSH
- rybí oleje farmakologie MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- studie případů a kontrol MeSH
- tukové emulze intravenózní farmakologie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
Long-chain n-3 polyunsaturated fatty acids modulate immune cell functions. The primary objective of this study was to evaluate the impact of different lipid emulsions (LEs) with supplemented doses of fish oil (FO) on serum cytokine concentration and in vitro cytokine production in patients with intestinal failure on home parenteral nutrition (HPNPs). We hypothesized that FO supplementation would diminish lipopolysaccharide (LPS)-stimulated cytokine production. Twelve HPNPs receiving Smoflipid for at least 3 months were given FO (Omegaven) for a further 4 weeks. After this cycle, the patients were randomized to subsequently receive 1 cycle with Lipoplus and 1 cycle with ClinOleic for 6 weeks or vice versa plus 4 weeks of added Omegaven after each cycle in a crossover design. Comparison of the baseline LE regimens showed lower LPS-stimulated production of IL-1β in the HPNPs on Lipoplus than on the Smoflipid and ClinOleic regimens, as well as lower IL-8 compared to the Smoflipid regimen. Omegaven reduced IL-8 concentration in serum under the Lipoplus regimen and diminished LPS-stimulated production of IL-1β under the Smoflipid and ClinOleic. IL-6 and TNF-α production was depressed only in those on Smoflipid. Irrespective of the LE used, the HPNPs compared to the healthy controls showed higher IL-6, IL-8, and TNF-α concentrations in serum and LPS-stimulated production of IL-6 as well as lower n-6/n-3 long-chain polyunsaturated fatty acids in the erythrocyte phospholipids. LPS-stimulated production of IL-6 correlated negatively with the parenteral dose of eicosapentaenoic acid + docosahexaenoic acid. In conclusion, FO-supplemented parenteral nutrition suppresses in vitro cytokine production.
Long-chain n-3 polyunsaturated fatty acids modulate immune cell functions. The primary objective of this study was to evaluate the impact of different lipid emulsions (LEs) with supplemented doses of fish oil (FO) on serum cytokine concentration and in vitro cytokine production in patients with intestinal failure on home parenteral nutrition (HPNPs). We hypothesized that FO supplementation would diminish lipopolysaccharide (LPS)-stimulated cytokine production. Twelve HPNPs receiving Smoflipid for at least 3 months were given FO (Omegaven) for a further 4 weeks. After this cycle, the patients were randomized to subsequently receive 1 cycle with Lipoplus and 1 cycle with ClinOleic for 6 weeks or vice versa plus 4 weeks of added Omegaven after each cycle in a crossover design. Comparison of the baseline LE regimens showed lower LPS-stimulated production of IL-1β in the HPNPs on Lipoplus than on the Smoflipid and ClinOleic regimens, as well as lower IL-8 compared to the Smoflipid regimen. Omegaven reduced IL-8 concentration in serum under the Lipoplus regimen and diminished LPS-stimulated production of IL-1β under the Smoflipid and ClinOleic. IL-6 and TNF-α production was depressed only in those on Smoflipid. Irrespective of the LE used, the HPNPs compared to the healthy controls showed higher IL-6, IL-8, and TNF-α concentrations in serum and LPS-stimulated production of IL-6 as well as lower n-6/n-3 long-chain polyunsaturated fatty acids in the erythrocyte phospholipids. LPS-stimulated production of IL-6 correlated negatively with the parenteral dose of eicosapentaenoic acid + docosahexaenoic acid. In conclusion, FO-supplemented parenteral nutrition suppresses in vitro cytokine production.
- MeSH
- cytokiny krev MeSH
- dospělí MeSH
- klinické křížové studie MeSH
- lidé středního věku MeSH
- lidé MeSH
- parenterální výživa doma metody MeSH
- potravní doplňky MeSH
- rybí oleje aplikace a dávkování krev farmakologie MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- techniky in vitro MeSH
- tukové emulze intravenózní aplikace a dávkování metabolismus farmakologie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- randomizované kontrolované studie MeSH
