BACKGROUND: Sodium-glucose cotransporter 2 inhibitors (SGLT-2i) are glucose-lowering agents used for the treatment of type 2 diabetes mellitus, which also improve heart failure and decrease the risk of cardiovascular complications. Epicardial adipose tissue (EAT) dysfunction was suggested to contribute to the development of heart failure. We aimed to elucidate a possible role of changes in EAT metabolic and inflammatory profile in the beneficial cardioprotective effects of SGLT-2i in subjects with severe heart failure. METHODS: 26 subjects with severe heart failure, with reduced ejection fraction, treated with SGLT-2i versus 26 subjects without treatment, matched for age (54.0 ± 2.1 vs. 55.3 ± 2.1 years, n.s.), body mass index (27.8 ± 0.9 vs. 28.8 ± 1.0 kg/m2, n.s.) and left ventricular ejection fraction (20.7 ± 0.5 vs. 23.2 ± 1.7%, n.s.), who were scheduled for heart transplantation or mechanical support implantation, were included in the study. A complex metabolomic and gene expression analysis of EAT obtained during surgery was performed. RESULTS: SGLT-2i ameliorated inflammation, as evidenced by the improved gene expression profile of pro-inflammatory genes in adipose tissue and decreased infiltration of immune cells into EAT. Enrichment of ether lipids with oleic acid noted on metabolomic analysis suggests a reduced disposition to ferroptosis, potentially further contributing to decreased oxidative stress in EAT of SGLT-2i treated subjects. CONCLUSIONS: Our results show decreased inflammation in EAT of patients with severe heart failure treated by SGLT-2i, as compared to patients with heart failure without this therapy. Modulation of EAT inflammatory and metabolic status could represent a novel mechanism behind SGLT-2i-associated cardioprotective effects in patients with heart failure.
- MeSH
- antiflogistika terapeutické užití farmakologie MeSH
- biologické markery krev MeSH
- diabetes mellitus 2. typu farmakoterapie metabolismus diagnóza MeSH
- epikardiální adipózní tkáň MeSH
- funkce levé komory srdeční účinky léků MeSH
- glifloziny * terapeutické užití farmakologie škodlivé účinky MeSH
- lidé středního věku MeSH
- lidé MeSH
- mediátory zánětu * metabolismus MeSH
- metabolomika MeSH
- perikard * metabolismus účinky léků MeSH
- srdeční selhání * metabolismus patofyziologie farmakoterapie MeSH
- stupeň závažnosti nemoci * MeSH
- tepový objem účinky léků MeSH
- tuková tkáň * účinky léků metabolismus MeSH
- výsledek terapie MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
Kromě známých probiotik a prebiotik se v odborné i laické literatuře čím dál častěji objevuje koncepce tzv. paraprobiotik a postbiotik. V obou připadech se jedná o produkty mikrobiální fermentace, kde není kladen důraz na přítomnost životaschopných mikroorganismů, ale přesto je očekáván výrazný pozitivní účinek na zdraví konzumenta. Zatímco paraprobiotika jsou inaktivované mikroorganismy, po‐ stbiotika jsou jejich metabolické produkty, např. kyselina mléčná a máselná, které samy o sobě vykazují mohutné fyziologické účinky a potenciál pozitivně ovlivnit naše zdraví. Mikrobní kultury, např. fermentované potraviny nám tedy mohou prospívat, i pokud neobsahují živé zárodky.
Along the well‐known probiotics and prebiotics, the concept of so‐called paraprobiotics and postbiotics appears more and more often in professional and popular literature. In both cases, these are products of microbial fermentation, where the presence of viable micro‐ organisms is not emphasized, but a significant positive effect on the health of the consumer is still expected. While paraprobiotics are inactivated microorganisms, postbiotics are their metabolic products, e.g. lactic and butyric acid, which in themselves show powerful physiological effects and the potential to positively influence our health. Microbial cultures, such as fermented foods, can therefore be‐ nefit us even if they do not contain live germs.
- Klíčová slova
- postbiotika,
- MeSH
- lidé MeSH
- probiotika * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
- Publikační typ
- abstrakt z konference MeSH
- Publikační typ
- abstrakt z konference MeSH
Metabolic transformation of cancer cells leads to the accumulation of lactate and significant acidification in the tumor microenvironment. Both lactate and acidosis have a well-documented impact on cancer progression and negative patient prognosis. Here, we report that cancer cells adapted to acidosis are significantly more sensitive to oxidative damage induced by hydrogen peroxide, high-dose ascorbate, and photodynamic therapy. Higher lactate concentrations abrogate the sensitization. Mechanistically, acidosis leads to a drop in antioxidant capacity caused by a compromised supply of nicotinamide adenine dinucleotide phosphate (NADPH) derived from glucose metabolism. However, lactate metabolism in the Krebs cycle restores NADPH supply and antioxidant capacity. CPI-613 (devimistat), an anticancer drug candidate, selectively eradicates the cells adapted to acidosis through inhibition of the Krebs cycle and induction of oxidative stress while completely abrogating the protective effect of lactate. Simultaneous cell treatment with tetracycline, an inhibitor of the mitochondrial proteosynthesis, further enhances the cytotoxic effect of CPI-613 under acidosis and in tumor spheroids. While there have been numerous attempts to treat cancer by neutralizing the pH of the tumor microenvironment, we alternatively suggest considering tumor acidosis as the Achilles' heel of cancer as it enables selective therapeutic induction of lethal oxidative stress.
- MeSH
- acidóza patofyziologie MeSH
- antitumorózní látky farmakologie MeSH
- citrátový cyklus účinky léků MeSH
- energetický metabolismus MeSH
- fyziologická adaptace MeSH
- glukosa metabolismus MeSH
- glykolýza MeSH
- kapryláty farmakologie MeSH
- koncentrace vodíkových iontů MeSH
- kyselina mléčná metabolismus MeSH
- lidé MeSH
- mitochondrie účinky léků metabolismus patologie MeSH
- nádorové buňky kultivované MeSH
- nádorové mikroprostředí * MeSH
- nádory farmakoterapie metabolismus patologie MeSH
- oxidační stres MeSH
- sulfidy farmakologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Postbiotics are health-promoting microbial metabolites delivered as a functional food or a food supplement. They either directly influence signaling pathways of the body or indirectly manipulate metabolism and the composition of intestinal microflora. Cancer is the second leading cause of death worldwide and even though the prognosis of patients is improving, it is still poor in the substantial part of the cases. The preventable nature of cancer and the importance of a complex multi-level approach in anticancer therapy motivate the search for novel avenues of establishing the anticancer environment in the human body. This review summarizes the principal findings demonstrating the usefulness of both natural and synthetic sources of postbotics in the prevention and therapy of cancer. Specifically, the effects of crude cell-free supernatants, the short-chain fatty acid butyrate, lactic acid, hydrogen sulfide, and β-glucans are described. Contradictory roles of postbiotics in healthy and tumor tissues are highlighted. In conclusion, the application of postbiotics is an efficient complementary strategy to combat cancer.
- MeSH
- beta-glukany farmakologie MeSH
- butyráty farmakologie MeSH
- kyselina mléčná farmakologie MeSH
- kyseliny mastné těkavé metabolismus farmakologie MeSH
- lidé MeSH
- metabolom MeSH
- nádory dietoterapie metabolismus MeSH
- potravní doplňky mikrobiologie MeSH
- prebiotika mikrobiologie MeSH
- probiotika metabolismus farmakologie MeSH
- střevní mikroflóra účinky léků MeSH
- sulfan farmakologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
For severe unconjugated hyperbilirubinemia the gold standard treatment is phototherapy with blue-green light, producing more polar photo-oxidation products, believed to be non-toxic. The aim of the present study was to compare the effects of bilirubin (BR) and lumirubin (LR), the major BR photo-oxidation product, on metabolic and oxidative stress markers. The biological activities of these pigments were investigated on several human and murine cell lines, with the focus on mitochondrial respiration, substrate metabolism, reactive oxygen species production, and the overall effects on cell viability. Compared to BR, LR was found to be much less toxic, while still maintaining a similar antioxidant capacity in the serum as well as suppressing activity leading to mitochondrial superoxide production. Nevertheless, due to its lower lipophilicity, LR was less efficient in preventing lipoperoxidation. The cytotoxicity of BR was affected by the cellular glycolytic reserve, most compromised in human hepatoblastoma HepG2 cells. The observed effects were correlated with changes in the production of tricarboxylic acid cycle metabolites. Both BR and LR modulated expression of PPARα downstream effectors involved in lipid and glucose metabolism. Proinflammatory effects of BR, evidenced by increased expression of TNFα upon exposure to bacterial lipopolysaccharide, were observed in murine macrophage-like RAW 264.7 cells. Collectively, these data point to the biological effects of BR and its photo-oxidation products, which might have clinical relevance in phototherapy-treated hyperbilirubinemic neonates and adult patients.
- Publikační typ
- časopisecké články MeSH
Inhibition of selected metabolic pathways is a hot topic in current cancer therapy. This is caused by the fact that metabolic transformation across different types of cancer cells is highly similar and, on the other hand, significantly different from the non-cancer cells. In this regard, glutamine is especially interesting because it serves not only as a donor of carbon skeletons and amino groups for the cell anabolism but also as a substrate involved in the energetic metabolism, redox homeostasis, and antioxidant protection. Therapeutic aiming at the glutamine metabolism offers a significant opportunity to improve the prognosis of cancer patients.
- MeSH
- glutamin * analýza farmakokinetika metabolismus MeSH
- nádorové procesy MeSH
- Publikační typ
- přehledy MeSH
Parenteral nutrition (PN) is often associated with the deterioration of liver functions (PNALD). Omega-3 polyunsaturated fatty acids (PUFA) were reported to alleviate PNALD but the underlying mechanisms have not been fully unraveled yet. Using omics´ approach, we determined serum and liver lipidome, liver proteome, and liver bile acid profile as well as markers of inflammation and oxidative stress in rats administered either ω-6 PUFA based lipid emulsion (Intralipid) or ω-6/ω-3 PUFA blend (Intralipid/Omegaven) via the enteral or parenteral route. In general, we found that enteral administration of both lipid emulsions has less impact on the liver than the parenteral route. Compared with parenterally administered Intralipid, PN administration of ω-3 PUFA was associated with 1. increased content of eicosapentaenoic (EPA)- and docosahexaenoic (DHA) acids-containing lipid species; 2. higher abundance of CYP4A isoenzymes capable of bioactive lipid synthesis and the increased content of their potential products (oxidized EPA and DHA); 3. downregulation of enzymes involved CYP450 drug metabolism what may represent an adaptive mechanism counteracting the potential negative effects (enhanced ROS production) of PUFA metabolism; 4. normalized anti-oxidative capacity and 5. physiological BAs spectrum. All these findings may contribute to the explanation of ω-3 PUFA protective effects in the context of PN.
- MeSH
- emulze MeSH
- enterální výživa metody MeSH
- fosfolipidy MeSH
- játra metabolismus MeSH
- krysa rodu rattus MeSH
- kyselina eikosapentaenová chemie MeSH
- kyseliny dokosahexaenové chemie MeSH
- kyseliny mastné omega-3 chemie MeSH
- kyslík metabolismus MeSH
- lipidomika MeSH
- lipidy chemie MeSH
- malondialdehyd metabolismus MeSH
- metabolomika MeSH
- nenasycené mastné kyseliny metabolismus MeSH
- oxidační stres MeSH
- parenterální výživa metody MeSH
- potkani Wistar MeSH
- proteom metabolismus MeSH
- reaktivní formy kyslíku metabolismus MeSH
- rybí oleje MeSH
- sójový olej MeSH
- zánět MeSH
- žlučové kyseliny a soli analýza MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- srovnávací studie MeSH
The normotensive (Wistar) and spontaneously hypertensive (SHR) rats were examined to assess the response of the organism to selenium (Se) overdose. Moreover, the effect of zinc (Zn) and vitamin E, i.e. dietary components interacting in many biochemical processes with Se, on the Se uptake was evaluated. The control group was fed an untreated diet, and the diets of two other groups were overdosed with Se in the form of sodium selenite (9 mg/kg) and supplemented with Zn (13 mg/kg). Two experimental groups were fed a diet supplemented with Zn (13 mg/kg) and Se at an adequate level (0.009 mg/kg); a half of the animals was supplemented with vitamin E. The results showed significant differences in the Se contents between the rat strains in case of Se-overdosed groups, where in the liver and kidney tissue Se contents of SHR rats exceeded 3- and 7-fold the normotensive ones. The Se uptake was altered by the vitamin E; no effect of Zn was observed. Activities of antioxidant enzymes were determined in the animal tissues indicating different patterns according to rat strain, tissue analysed, and administered Se dose. Thus, Se overdose, for instance, via an incorrectly prepared dietary supplement, can result in serious imbalances of the biochemical status of the animals.
- MeSH
- antioxidancia aplikace a dávkování terapeutické užití MeSH
- kombinovaná farmakoterapie MeSH
- krysa rodu rattus MeSH
- potkani inbrední SHR MeSH
- potkani inbrední WKY MeSH
- potravní doplňky MeSH
- předávkování léky farmakoterapie metabolismus MeSH
- selen aplikace a dávkování toxicita MeSH
- stopové prvky aplikace a dávkování terapeutické užití toxicita MeSH
- vitamin E aplikace a dávkování terapeutické užití MeSH
- zinek aplikace a dávkování terapeutické užití MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
