Zucker fatty (fa/fa) rats represent a well-established and widely used model of genetic obesity. Because previous metabolomic studies have only been published for young fa/fa rats up to 20 weeks of age, which can be considered early maturity in male fa/fa rats, the aim of our work was to extend the metabolomic characterization to significantly older animals. Therefore, the urinary profiles of obese fa/fa rats and their lean controls were monitored using untargeted NMR metabolomics between 12 and 40 weeks of age. At the end of the experiment, the rats were also characterized by NMR and LC-MS serum analysis, which was supplemented by a targeted LC-MS analysis of serum bile acids and neurotransmitters. The urine analysis showed that most of the characteristic differences detected in young obese fa/fa rats persisted throughout the experiment, primarily through a decrease in microbial co-metabolite levels, the upregulation of the citrate cycle, and changes in nicotinamide metabolism compared with the age-related controls. The serum of 40-week-old obese rats showed a reduction in several bile acid conjugates and an increase in serotonin. Our study demonstrated that the fa/fa model of genetic obesity is stable up to 40 weeks of age and is therefore suitable for long-term experiments.
- Publikační typ
- časopisecké články MeSH
Type 1 diabetes (T1D) is an autoimmune disease with rising incidence. Pre- and manifest T1D is associated with intestinal barrier dysfunction, skewed microbiota composition, and serum dyslipidemia. The intestinal mucus layer protects against pathogens and its structure and phosphatidylcholine (PC) lipid composition may be compromised in T1D, potentially contributing to barrier dysfunction. This study compared prediabetic Non-Obese Diabetic (NOD) mice to healthy C57BL/6 mice by analyzing the intestinal mucus PC profile by shotgun lipidomics, plasma metabolomics by mass spectrometry and nuclear magnetic resonance, intestinal mucus production by histology, and cecal microbiota composition by 16 S rRNA sequencing. Jejunal mucus PC class levels were decreased in early prediabetic NOD vs C57BL/6 mice. In colonic mucus of NOD mice, the level of several PC species was reduced throughout prediabetes. In plasma, similar reductions of PC species were observed in early prediabetic NOD mice, where also increased beta-oxidation was prominent. No histological alterations were found in jejunal nor colonic mucus between the mouse strains. However, the β-diversity of the cecal microbiota composition differed between prediabetic NOD and C57BL/6 mice, and the bacterial species driving this difference were related to decreased short-chain fatty acid (SCFA)-production in the NOD mice. This study reports reduced levels of PCs in the intestinal mucus layer and plasma of prediabetic NOD mice as well as reduced proportions of SCFA-producing bacteria in cecal content at early prediabetes, possibly contributing to intestinal barrier dysfunction and T1D.
- MeSH
- diabetes mellitus 1. typu * MeSH
- fosfatidylcholiny MeSH
- hlen MeSH
- myši inbrední C57BL MeSH
- myši inbrední NOD MeSH
- myši MeSH
- prediabetes * MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Anorexia nervosa (AN), a pathological restriction of food intake, leads to metabolic dysregulation. We conducted a metabolomics study to reveal changes caused by AN and the effect of hospital realimentation on metabolism. Both stool and serum from patients with AN and healthy controls were analyzed by NMR and MS. Statistical analysis revealed several altered biochemical and anthropometric parameters and 50 changed metabolites, including phospholipids, acylcarnitines, amino acids, derivatives of nicotinic acid, nucleotides, and energy metabolism intermediates. Biochemical and anthropometric parameters were correlated with metabolomic data. Metabolic changes in patients with AN described in our study imply serious system disruption defects, such as the development of inflammation and oxidative stress, changed free thyroxine (fT4) and thyroid-stimulating hormone (TSH) levels, a deficit of vitamins, muscle mass breakdown, and a decrease in ketone bodies as an important source of energy for the brain and heart. Furthermore, our data indicate only a very slight improvement after treatment. However, correlations of metabolomic results with body weight, interleukin 6, tumor necrosis factor α, fT4, and TSH might entail better prognoses and treatment effectiveness in patients with better system parameter status. Data sets are deposited in MassIVE: MSV000087713, DOI: 10.25345/C57R7X.
Východisko: V patogeneze cholesterolové cholelitiázy (gallstone disease – GD) se uplatňuje především supersaturace žluči cholesterolem (i), hypomobilita žlučníku (ii) a poruchy nukleace žluči (iii). Biliární cholesterol a žlučové kyseliny (bile acids – BA) pocházejí pouze z 10 % z cholesterolu syntetizovaného de novo, biliární cholesterol je tvořen především z HDL-cholesterolu a BA z LDL-cholesterolu. BA solubilizují žlučový cholesterol a jako signální molekuly ovlivňují řadu pochodů (syntéza primárních BA, regulace homeostázy lipidů, glukózy a energetického metabolizmu). Cíl práce: Analyzovat vztahy koncentrací žlučníkových a plazmatických BA u pacientů s GD (i) a dále porovnat koncentrace plazmatických BA u osob s cholesterolovou GD a kontrolních osob (ii). Materiál a metody: U 41 osob s cholesterolovou GD jsme analyzovali koncentrace plazmatických a žlučníkových BA nalačno a plazmatické BA u 49 osob kontrolní skupiny (KON). BA byly měřeny hmotnostní spektroskopií. Všichni pacienti byli standardně klinicky a biochemicky vyšetřeni. Výsledky: Skupina s GD měla vyšší věk (58,8 vs 45,5 let; GD vs KON; P = 0,001); skupiny se nelišily zastoupením mužů. Pacienti s GD měli vyšší koncentrace celkového cholesterolu a LDL-cholesterolu (3,17 vs 2,44 mmol/l; GD vs KON, P = 0,001) a glykémie (5,66 vs 4,85 mmol/l; GD vs KON, mmol/l; P = 0,001). Mezi koncentrací plazmatických a žlučníkových BA jsme prokázali významné korelace pro kyselinu chenodeoxycholovou, ursodeoxycholovou a litocholovou (P < 0,001). Korelace mezi koncentrací kyseliny cholové v plazmě a žluči nebyly významné. Kontrolní skupina měla vyšší koncentrace celkových, primárních, sekundárních i volných žlučových kyselin (P < 0,01). Závěry: Vyšší koncentrace plazmatických BA u kontrolní skupiny pravděpodobně reflektují větší tělesný pool žlučových kyselin a v jeho důsledku i vyšší solubilizační kapacitu pro cholesterol secernovaný do žluče.
- 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
- Publikační typ
- abstrakt z konference MeSH
Brain-gut microbiota interactions are intensively studied in connection with various neurological and psychiatric diseases. While anorexia nervosa (AN) pathophysiology is not entirely clear, it is presumably linked to microbiome dysbiosis. We aimed to elucidate the gut microbiota contribution in AN disease pathophysiology. We analyzed the composition and diversity of the gut microbiome of patients with AN (bacteriome and mycobiome) from stool samples before and after renourishment, and compared them to healthy controls. Further, levels of assorted neurotransmitters and short-chain fatty acids (SCFA) were analyzed in stool samples by MS and NMR, respectively. Biochemical, anthropometric, and psychometric profiles were assessed. The bacterial alpha-diversity parameter analyses revealed only increased Chao 1 index in patients with AN before the realimentation, reflecting their interindividual variation. Subsequently, core microbiota depletion signs were observed in patients with AN. Overrepresented OTUs (operation taxonomic units) in patients with AN taxonomically belonged to Alistipes, Clostridiales, Christensenellaceae, and Ruminococcaceae. Underrepresented OTUs in patients with AN were Faecalibacterium, Agathobacter, Bacteroides, Blautia, and Lachnospira. Patients exhibited greater interindividual variation in the gut bacteriome, as well as in metagenome content compared to controls, suggesting altered bacteriome functions. Patients had decreased levels of serotonin, GABA, dopamine, butyrate, and acetate in their stool samples compared to controls. Mycobiome analysis did not reveal significant differences in alpha diversity and fungal profile composition between patients with AN and healthy controls, nor any correlation of the fungal composition with the bacterial profile. Our results show the changed profile of the gut microbiome and its metabolites in patients with severe AN. Although therapeutic partial renourishment led to increased body mass index and improved psychometric parameters, SCFA, and neurotransmitter profiles, as well as microbial community compositions, did not change substantially during the hospitalization period, which can be potentially caused by only partial weight recovery.
- MeSH
- Archaea klasifikace růst a vývoj MeSH
- Bacteria klasifikace růst a vývoj metabolismus MeSH
- dospělí MeSH
- feces mikrobiologie MeSH
- houby klasifikace růst a vývoj metabolismus MeSH
- index tělesné hmotnosti MeSH
- kyseliny mastné těkavé metabolismus MeSH
- lidé MeSH
- longitudinální studie MeSH
- mentální anorexie metabolismus mikrobiologie MeSH
- metagenom MeSH
- mladý dospělý MeSH
- mykobiom MeSH
- neurotransmiterové látky metabolismus MeSH
- osa mozek-střevo MeSH
- střevní mikroflóra * MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- mladý dospělý MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Publikační typ
- abstrakt z konference MeSH
Coronary artery disease is one of the most frequent causes of morbidity and mortality worldwide. It is even more prevalent in patients with type 2 diabetes mellitus who suffer from obesity and increased accumulation of epicardial fat with a possible contributing role in the development of coronary artery disease. We performed an MS-based lipidomic analysis of subcutaneous and epicardial adipose tissue in 23 patients with coronary artery disease stratified for the presence/absence of type 2 diabetes mellitus and a control group of 13 subjects aiming at identification of factors from epicardial fat contributing to the development of coronary artery disease. The samples of adipose tissues were obtained during elective cardiac surgery. They were extracted and analyzed with and without previous triacylglycerols separation by high-pressure liquid chromatography-mass spectrometry (HPLC-MS). Multivariate and univariate analyses were performed. Lipidomics data were correlated with biochemical parameters. We identified multiple changes in monoacylglycerols, diacylglycerols, triacylglycerols, glycerophosphatidylserines, glycerophosphatidylethanolamines, glycerophosphatidylcholines, ceramides, sphingomyelins, and derivatives of cholesterol. Observed changes included molecules with fatty acids with odd (15:0, 15:1, 17:0, 17:1) and even (10:0, 12:0, 14:0, 16:0, 16:1, 18:0, 18:1, 18:2, 20:4, 20:1, 22:0) fatty acids in both types of adipose tissue. More pronounced changes were detected in epicardial adipose tissue compared to subcutaneous adipose tissue of patients with coronary artery disease and type 2 diabetes. Lipidomic analysis of subcutaneous and epicardial adipose tissue revealed different profiles for patients with coronary artery disease and type 2 diabetes, which might be related to coronary artery disease and the presence of type 2 diabetes.
- MeSH
- diabetes mellitus 2. typu * MeSH
- lidé MeSH
- lipidy MeSH
- nemoci koronárních tepen * MeSH
- perikard MeSH
- podkožní tuk MeSH
- tuková tkáň MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
