α-Tocopheryl succinate (α-TOS) is a promising anti-cancer agent due to its selectivity for cancer cells. It is important to understand whether long-term exposure of tumour cells to the agent will render them resistant to the treatment. Exposure of the non-small cell lung carcinoma H1299 cells to escalating doses of α-TOS made them resistant to the agent due to the upregulation of the ABCA1 protein, which caused its efflux. Full susceptibility of the cells to α-TOS was restored by knocking down the ABCA1 protein. Similar resistance including ABCA1 gene upregulation was observed in the A549 lung cancer cells exposed to α-TOS. The resistance of the cells to α-TOS was overcome by its mitochondrially targeted analogue, MitoVES, that is taken up on the basis of the membrane potential, bypassing the enhanced expression of the ABCA1 protein. The in vitro results were replicated in mouse models of tumours derived from parental and resistant H1299 cells. We conclude that long-term exposure of cancer cells to α-TOS causes their resistance to the drug, which can be overcome by its mitochondrially targeted counterpart. This finding should be taken into consideration when planning clinical trials with vitamin E analogues.

• MeSH
• ABC transportéry genetika   fyziologie   MeSH
• ABCA1 protein MeSH
• alfa-tokoferol terapeutické užití   MeSH
• chemorezistence * MeSH
• genový knockdown MeSH
• mitochondrie účinky léků   MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• nádory plic farmakoterapie   MeSH
• nemalobuněčný karcinom plic farmakoterapie   MeSH
• protinádorové látky farmakologie   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Single nucleotide polymorphisms located in 5' untranslated regions (5'UTRs) can regulate gene expression and have clinical impact. Recognition of functionally significant sequences within 5'UTRs is crucial in next-generation sequencing applications. Furthermore, information about the behavior of 5'UTRs during gene evolution is scarce. Using the example of the ATP-binding cassette transporter A1 (ABCA1) gene (Tangier disease), we describe our algorithm for functionally significant sequence finding. 5'UTR features (upstream start and stop codons, open reading frames (ORFs), GC content, motifs, and secondary structures) were studied using freely available bioinformatics tools in 55 vertebrate orthologous genes obtained from Ensembl and UCSC. The most conserved sequences were suggested as hot spots. Exon and intron enhancers and silencers (sc35, ighg2 cgamma2, ctnt, gh-1, and fibronectin eda exon), transcription factors (TFIIA, TATA, NFAT1, NFAT4, and HOXA13), some of them cancer related, and microRNA (hsa-miR-4474-3p) were localized to these regions. An upstream ORF, overlapping with the main ORF in primates and possibly coding for a small bioactive peptide, was also detected. Moreover, we showed several features of 5'UTRs, such as GC content variation, hairpin structure conservation or 5'UTR segmentation, which are interesting from a phylogenetic point of view and can stimulate further evolutionary oriented research.

• MeSH
• 5' nepřekládaná oblast * genetika   MeSH
• ABCA1 protein chemie   genetika   MeSH
• anotace sekvence MeSH
• fylogeneze MeSH
• introny MeSH
• konformace nukleové kyseliny MeSH
• konzervovaná sekvence genetika   MeSH
• lidé MeSH
• messenger RNA genetika   metabolismus   MeSH
• nukleotidové motivy genetika   MeSH
• otevřené čtecí rámce genetika   MeSH
• savci genetika   MeSH
• sekvence aminokyselin MeSH
• sekvence nukleotidů MeSH
• sestřih RNA genetika   MeSH
• zastoupení bazí genetika   MeSH
• zesilovače transkripce genetika   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH

We and others have recently identified mutations in the ABCA1 gene as the underlying cause of Tangier disease (TD) and of a dominantly inherited form of familial hypoalphalipoproteinemia (FHA) associated with reduced cholesterol efflux. We have now identified 13 ABCA1 mutations in 11 families (five TD, six FHA) and have examined the phenotypes of 77 individuals heterozygous for mutations in the ABCA1 gene. ABCA1 heterozygotes have decreased HDL cholesterol (HDL-C) and increased triglycerides. Age is an important modifier of the phenotype in heterozygotes, with a higher proportion of heterozygotes aged 30-70 years having HDL-C greater than the fifth percentile for age and sex compared with carriers less than 30 years of age. Levels of cholesterol efflux are highly correlated with HDL-C levels, accounting for 82% of its variation. Each 8% change in ABCA1-mediated efflux is predicted to be associated with a 0.1 mmol/l change in HDL-C. ABCA1 heterozygotes display a greater than threefold increase in the frequency of coronary artery disease (CAD), with earlier onset than unaffected family members. CAD is more frequent in those heterozygotes with lower cholesterol efflux values. These data provide direct evidence that impairment of cholesterol efflux and consequently reverse cholesterol transport is associated with reduced plasma HDL-C levels and increased risk of CAD.

• MeSH
• ABC transportéry * genetika   metabolismus   MeSH
• biologický transport MeSH
• cholesterol * metabolismus   MeSH
• dospělí MeSH
• fenotyp MeSH
• HDL-cholesterol * metabolismus   MeSH
• heterozygot * MeSH
• index tělesné hmotnosti MeSH
• koronární nemoc genetika   metabolismus   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mutace MeSH
• rizikové faktory MeSH
• senioři MeSH
• sexuální faktory MeSH
• tangierská nemoc * genetika   metabolismus   MeSH
• triglyceridy metabolismus   MeSH
• věkové faktory MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• práce podpořená grantem MeSH

• Publikační typ
• abstrakty MeSH

• MeSH
• 5' nepřekládaná oblast fyziologie   genetika   MeSH
• ABC transportéry genetika   MeSH
• infarkt myokardu genetika   MeSH
• lidé MeSH
• lipidy krev   MeSH
• polymorfismus genetický genetika   MeSH
• promotorové oblasti (genetika) imunologie   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• srovnávací studie MeSH

AIMS: The effects of cholesteryl ester transfer protein (CETP) inhibition on lipids, inflammation, and markers of high-density lipoprotein (HDL) function, following an acute coronary syndrome (ACS), are unknown. METHODS AND RESULTS: The dal-ACUTE study randomized 300 patients (1 : 1) to dalcetrapib 600 mg/day or placebo within 1 week of an ACS. The primary endpoint was per cent change in HDL-cholesterol (HDL-C) after 4 weeks. Secondary endpoints included apolipoprotein levels, markers of HDL function, and inflammation. Dalcetrapib treatment increased HDL-C and apolipoprotein A1 by 33.7 and 11.8%, respectively (both P < 0.001) and total cholesterol efflux by 9.5% (P = 0.003) after 4 weeks, principally via an increase in non-ATP-binding cassette transporter (ABC) A1-mediated efflux, without statistically significant changes in pre-β1-HDL levels. The increase in total efflux with dalcetrapib correlated most strongly with increases in apolipoprotein A1 and HDL-C (r = 0.46 and 0.43, respectively) rather than the increase in pre-β1-HDL (r = 0.32). Baseline and on-treatment ABCA1-mediated efflux correlated most strongly with pre-β1-HDL levels; in contrast, non-ABCA1-mediated efflux correlated better with apolipoprotein A1 and HDL-C levels. CONCLUSIONS: High-density lipoprotein raised through CETP inhibition with dalcetrapib improves cholesterol efflux, principally via a non-ABCA1-mediated pathway. While HDL-C was increased by one-third, apolipoprotein A1 and total efflux were increased only by one-tenth, supporting the concept of dissociation between improvements in HDL function and HDL-C levels, which may be of relevance to ongoing trials and the development of therapeutic interventions targeting HDL.

• MeSH
• ABCA1 protein metabolismus   MeSH
• akutní koronární syndrom farmakoterapie   MeSH
• anticholesteremika aplikace a dávkování   MeSH
• apolipoproteiny metabolismus   MeSH
• biologické markery metabolismus   MeSH
• C-reaktivní protein metabolismus   MeSH
• dvojitá slepá metoda MeSH
• HDL-cholesterol metabolismus   MeSH
• infarkt myokardu farmakoterapie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• lipoproteiny metabolismus   MeSH
• metabolismus lipidů účinky léků   MeSH
• nestabilní angina pectoris farmakoterapie   MeSH
• rozvrh dávkování léků MeSH
• sulfhydrylové sloučeniny aplikace a dávkování   MeSH
• transportní proteiny pro estery cholesterolu antagonisté a inhibitory   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH

• MeSH
• ABC transportéry genetika   izolace a purifikace   metabolismus   MeSH
• ABCA1 protein genetika   izolace a purifikace   metabolismus   MeSH
• experimenty na zvířatech MeSH
• financování organizované MeSH
• hypolipidemika metabolismus   MeSH
• krysa rodu rattus MeSH
• messenger RNA izolace a purifikace   metabolismus   účinky léků   MeSH
• nenasycené mastné kyseliny metabolismus   MeSH
• omega-3 mastné kyseliny * metabolismus   terapeutické užití   MeSH
• silymarin * metabolismus   terapeutické užití   MeSH
• statistika jako téma MeSH
• transportní proteiny * izolace a purifikace   metabolismus   účinky léků   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH

Leoligin is a natural lignan found in Edelweiss (Leontopodium nivale ssp. alpinum). The aim of this study was to examine its influence on cholesterol efflux and to address the underlying mechanism of action. Leoligin increases apo A1- as well as 1% human plasma-mediated cholesterol efflux in THP-1 macrophages without affecting cell viability as determined by resazurin conversion. Western blot analysis revealed that the protein levels of the cholesterol efflux transporters ABCA1 and ABCG1 were upregulated, whereas the SR-B1 protein level remained unchanged upon treatment with leoligin (10 μM, 24 h). Quantitative reverse transcription PCR further uncovered that leoligin also increased ABCA1 and ABCG1 mRNA levels without affecting the half-life of the two mRNAs in the presence of actinomycin D, a transcription inhibitor. Proteome analysis revealed the modulation of protein expression fingerprint in the presence of leoligin. Taken together, these results suggest that leoligin induces cholesterol efflux in THP-1-derived macrophages by upregulating ABCA1 and ABCG1 expression. This novel activity suggests leoligin as a promising candidate for further studies addressing a possible preventive or therapeutic application in the context of atherosclerosis.

• MeSH
• ABC transportéry metabolismus   MeSH
• Asteraceae chemie   MeSH
• ateroskleróza MeSH
• biologický transport MeSH
• daktinomycin farmakologie   MeSH
• lidé MeSH
• lignany chemie   izolace a purifikace   farmakologie   MeSH
• makrofágy metabolismus   MeSH
• messenger RNA metabolismus   MeSH
• molekulární struktura MeSH
• oxaziny metabolismus   MeSH
• polymerázová řetězová reakce MeSH
• sirotčí receptory metabolismus   MeSH
• western blotting MeSH
• xantheny metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

OBJECTIVES: The aim of our study was to assess the association of common sequence variants, and selected interactions, with HDL-c plasma levels. DESIGN AND METHODS: We analysed 743 individuals (340 men and 403 women) with high mean triglyceride and LDL-c levels. The association of five polymorphic sites (ABCA1 g.1051G>A, APOA1 g.-75G>A, CETP g.-629C>A, HNF1A g.102A>C, and LIPG g.584C>T), apoE isoforms and selected interactions with HDL-c levels were evaluated using linear regression models. RESULTS: After adjusting for triglycerides, sex, and BMI the only genotype with a statistically significant effect on HDL-c levels (p-value=0.004) was the CETP promoter variant. Further, linear regression model with interactions included indicated possible interplay between APOA1 genotype and menopause (p-value=0.002) and ABCA1 and APOE isoforms (p-value=0.017) on HDL-c plasma concentration. CONCLUSIONS: Our study indicated that not only the CETP variant but also apoE isoforms and menopause could operate as potent modulators of HDL-c concentrations.

• MeSH
• apolipoproteiny E MeSH
• dospělí MeSH
• genotyp MeSH
• HDL-cholesterol krev   MeSH
• jednonukleotidový polymorfismus MeSH
• LDL-cholesterol krev   MeSH
• lidé středního věku MeSH
• lidé MeSH
• menopauza MeSH
• protein - isoformy MeSH
• rizikové faktory MeSH
• transportní proteiny pro estery cholesterolu genetika   MeSH
• triglyceridy krev   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Aim: Development of type 2 diabetes (T2DM) is associated with disturbances in immune and metabolic status that may be reflected by an altered gene expression profile of peripheral blood mononuclear cells (PBMC). To reveal a potential family predisposition to these alterations, we investigated the regulation of gene expression profiles in circulating CD14+ and CD14- PBMC in fasting conditions and in response to oral glucose tolerance test (OGTT) in glucose tolerant first-degree relatives (FDR) of T2DM patients and in control subjects. Materials and Methods: This work is based on the clinical study LIMEX (NCT03155412). Non-obese 12 non-diabetic (FDR), and 12 control men without family history of diabetes matched for age and BMI underwent OGTT. Blood samples taken before and at the end of OGTT were used for isolation of circulating CD14+ and CD14- PBMC. In these cells, mRNA levels of 94 genes related to lipid and carbohydrate metabolism, immunity, and inflammation were assessed by qPCR. Results: Irrespectively of the group, the majority of analyzed genes had different mRNA expression in CD14+ PBMC compared to CD14- PBMC in the basal (fasting) condition. Seven genes (IRS1, TLR2, TNFα in CD14+ PBMC; ABCA1, ACOX1, ATGL, IL6 in CD14- PBMC) had different expression in control vs. FDR groups. OGTT regulated mRNA levels of nine genes selectively in CD14+ PBMC and of two genes (ABCA1, PFKL) selectively in CD14-PBMC. Differences in OGTT-induced response between FDR and controls were observed for EGR2, CCL2 in CD14+ PBMC and for ABCA1, ACOX1, DGAT2, MLCYD, and PTGS2 in CD14- PBMC. Conclusion: This study revealed a different impact of glucose challenge on gene expression in CD14+ when compared with CD14- PBMC fractions and suggested possible impact of family predisposition to T2DM on basal and OGTT-induced gene expression in these PBMC fractions. Future studies on these putative alterations of inflammation and lipid metabolism in fractionated PBMC in larger groups of subjects are warranted.

• MeSH
• biologické markery metabolismus   MeSH
• diabetes mellitus 2. typu genetika   metabolismus   patologie   MeSH
• dospělí MeSH
• genetická predispozice k nemoci * MeSH
• glukózový toleranční test MeSH
• krevní glukóza analýza   MeSH
• leukocyty mononukleární metabolismus   patologie   MeSH
• lidé MeSH
• lipopolysacharidové receptory metabolismus   MeSH
• regulace genové exprese * MeSH
• studie případů a kontrol MeSH
• transkriptom * MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH