Wilson disease (WD) primarily presents with hepatic and neurological symptoms. While hepatic symptoms typically precede the neurological manifestations, copper accumulates in the brain already in this patient group and leads to subclinical brain MRI abnormalities including T2 hyperintensities and atrophy. This study aimed to assess brain morphological changes in mild hepatic WD. WD patients without a history of neurologic symptoms and decompensated cirrhosis and control participants underwent brain MRI at 3T scanner including high-resolution T1-weighted images. A volumetric evaluation was conducted on the following brain regions: nucleus accumbens, caudate, pallidum, putamen, thalamus, amygdala, hippocampus, midbrain, pons, cerebellar gray matter, white matter (WM), and superior peduncle, using Freesurfer v7 software. Whole-brain analyses using voxel- and surface-based morphometry were performed using SPM12. Statistical comparisons utilized a general linear model adjusted for total intracranial volume, age, and sex. Twenty-six WD patients with mild hepatic form (30 ± 9 years [mean age ± SD]); 11 women; mean treatment duration 13 ± 12 (range 0-42) years and 28 healthy controls (33 ± 9 years; 15 women) were evaluated. Volumetric analysis revealed a significantly smaller pons volume and a trend for smaller midbrain and cerebellar WM in WD patients compared to controls. Whole-brain analysis revealed regions of reduced volume in the pons, cerebellar, and lobar WM in the WD group. No significant differences in gray matter density or cortical thickness were found. Myelin or WM in general seems vulnerable to low-level copper toxicity, with WM volume loss showing promise as a marker for assessing brain involvement in early WD stages.
- MeSH
- bílá hmota patologie diagnostické zobrazování MeSH
- dospělí MeSH
- hepatolentikulární degenerace * patologie diagnostické zobrazování MeSH
- játra patologie diagnostické zobrazování MeSH
- lidé středního věku MeSH
- lidé MeSH
- magnetická rezonanční tomografie * MeSH
- mladý dospělý MeSH
- mozek * patologie diagnostické zobrazování MeSH
- šedá hmota patologie diagnostické zobrazování MeSH
- studie případů a kontrol MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Alterations in tricarboxylic acid (TCA) cycle metabolism are associated with hepatic metabolic disorders. Elevated hepatic acetate concentrations, often attributed to high caloric intake, are recognized as a pivotal factor in the etiology of obesity and metabolic syndrome. Therefore, the assessment of acetate breakdown and TCA cycle activity plays a central role in understanding the impact of diet-induced alterations on liver metabolism. Magnetic resonance-based deuterium metabolic imaging (DMI) could help to unravel the underlying mechanisms involved in disease development and progression, however, the application of conventional deuterated glucose does not lead to substantial enrichment in hepatic glutamine and glutamate. This study aimed to demonstrate the feasibility of DMI for tracking deuterated acetate breakdown via the TCA cycle in lean and diet-induced fatty liver (FL) rats using 3D DMI after an intraperitoneal infusion of sodium acetate-d3 at 9.4T. Localized and nonlocalized liver spectra acquired at 10 time points post-injection over a 130-min study revealed similar intrahepatic acetate uptake in both animal groups (AUCFL = 717.9 ± 131.1 mM▯min-1, AUClean = 605.1 ± 119.9 mM▯min-1, p = 0.62). Metabolic breakdown could be observed in both groups with an emerging glutamine/glutamate (Glx) peak as a downstream metabolic product (AUCFL = 113.6 ± 23.8 mM▯min-1, AUClean = 136.7 ± 41.7 mM▯min-1, p = 0.68). This study showed the viability of DMI for tracking substrate flux through the TCA cycle, underscoring its methodological potential for imaging metabolic processes in the body.
- MeSH
- acetáty metabolismus MeSH
- analýza metabolického toku MeSH
- citrátový cyklus * MeSH
- deuterium * MeSH
- játra * metabolismus diagnostické zobrazování MeSH
- krysa rodu rattus MeSH
- magnetická rezonanční tomografie MeSH
- potkani Sprague-Dawley MeSH
- potkani Wistar MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Background/Objectives: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a growing global health problem closely linked to dietary habits, particularly high fructose consumption. This study investigates the combined effects of fructose and common food preservatives (sodium benzoate, sodium nitrite, and potassium sorbate) on the development and progression of MASLD. Methods: We utilized a human microbiota-associated mouse model, administering 10% fructose with or without preservatives for 11 weeks. Liver histology, hepatic gene expression (microarray analysis), biochemical markers, cytokine profiles, intestinal permeability, and gut microbiome composition (16S rRNA and Internal Transcribed Spacer (ITS) sequencing) were evaluated. Results: Fructose and potassium sorbate synergistically induced liver pathology characterized by increased steatosis, inflammation and fibrosis. These histological changes were associated with elevated liver function markers and altered lipid profiles. The treatments also induced significant changes in both the bacterial and fungal communities and disrupted intestinal barrier function, leading to increased pro-inflammatory responses in the mesenteric lymph nodes. Liver gene expression analysis revealed a wide range of transcriptional changes induced by fructose and modulated by the preservative. Key genes involved in lipid metabolism, oxidative stress, and inflammatory responses were affected. Conclusions: Our findings highlight the complex interactions between dietary components, gut microbiota, and host metabolism in the development of MASLD. The study identifies potential risks associated with the combined consumption of fructose and preservatives, particularly potassium sorbate. Our data reveal new mechanisms that are involved in the development of MASLD and open up a new avenue for the prevention and treatment of MASLD through dietary interventions and the modulation of the microbiome.
- MeSH
- exprese genu účinky léků MeSH
- fruktosa * škodlivé účinky MeSH
- játra * metabolismus účinky léků MeSH
- kyselina sorbová farmakologie MeSH
- modely nemocí na zvířatech MeSH
- myši inbrední C57BL MeSH
- myši MeSH
- potravinářské konzervační látky * farmakologie škodlivé účinky MeSH
- střevní mikroflóra * účinky léků MeSH
- synergismus léků MeSH
- ztučnělá játra MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
BACKGROUND: Schistosoma mansoni was introduced from Africa to the Americas during the transatlantic slave trade and remains a major public health problem in parts of South America and the Caribbean. This study presents a comprehensive comparative analysis of three S. mansoni strains with different geographical origins-from Liberia, Belo Horizonte and Puerto Rico. We demonstrated significant variation in virulence and host-parasite interactions. METHODS: We investigated the phenotypic characteristics of the parasite and its eggs, as well as the immunopathologic effects on laboratory mouse organ systems. RESULTS: Our results show significant differences in worm morphology, worm burden, egg size, and pathologic organ changes between these strains. The Puerto Rican strain showed the highest virulence, as evidenced by marked liver and spleen changes and advanced liver fibrosis indicated by increased collagen content. In contrast, the strains from Liberia and Belo Horizonte had a less pathogenic profile with less liver fibrosis. We found further variations in granuloma formation, cytokine expression and T-cell dynamics, indicating different immune responses. CONCLUSION: Our study emphasizes the importance of considering intra-specific variations of S. mansoni for the development of targeted therapies and public health strategies. The different virulence patterns, host immune responses and organ pathologies observed in these strains provide important insights for future research and could inform region-specific interventions for schistosomiasis control.
- MeSH
- cytokiny metabolismus MeSH
- interakce hostitele a parazita MeSH
- játra * parazitologie patologie MeSH
- myši MeSH
- Schistosoma mansoni * patogenita genetika imunologie MeSH
- schistosomiasis mansoni * parazitologie imunologie patologie MeSH
- slezina parazitologie patologie imunologie MeSH
- virulence MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Geografické názvy
- Libérie MeSH
- Portoriko MeSH
BACKGROUND AND AIMS: Prolonged fasting, which leads to the mobilization of fat from adipose tissue, can result in the development of hepatosteatosis. However, it is not yet known whether the accumulation of fat in the liver after fasting can be affected by concurrent obesity. Therefore, this study aimed to assess how excessive adiposity influences changes in liver fat content induced by fasting and subsequent refeeding. METHODS AND RESULTS: Ten lean women and eleven women with obesity (age: 36.4 ± 7.9 and 34.5 ± 7.9 years, BMI: 21.4 ± 1.7 and 34.5 ± 4.8 kg/m2) underwent a 60-h fasting period followed by 2 days of isocaloric high-carbohydrate refeeding. Magnetic resonance spectroscopy (MRS) examinations of liver were conducted at baseline, after 48 h of fasting, and at the end of refeeding period. Hepatic fat content (HFC) increased in lean women after fasting, whereas no statistically significant change in HFC was observed in women with obesity. Additionally, fasting led to significant reductions in liver volume in both groups, likely attributable to glycogen depletion, with subsequent restoration upon refeeding. Notably, changes in hepatic fat volume (HFV) rather than HFC inversely correlated with baseline liver fat content and HOMA-IR. CONCLUSION: We demonstrated that prolonged fasting results in accumulation of fat in the liver in lean subjects only and that this accumulation is inversely related to baseline fat content and insulin resistance. Moreover, the study underscored the importance of evaluating hepatic fat volume rather than hepatic fat content in studies that involve considerable changes in hepatic lean volume.
- MeSH
- adipozita * MeSH
- časové faktory MeSH
- dietní sacharidy aplikace a dávkování MeSH
- dospělí MeSH
- játra * metabolismus diagnostické zobrazování MeSH
- lidé středního věku MeSH
- lidé MeSH
- obezita * patofyziologie terapie metabolismus MeSH
- omezení příjmu potravy * MeSH
- sacharidová dieta škodlivé účinky MeSH
- studie případů a kontrol MeSH
- ztučnělá játra diagnostické zobrazování MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- srovnávací studie MeSH
Lenvatinib is an orally effective tyrosine kinase inhibitor used to treat several types of tumors, including progressive, radioiodine-refractory differentiated thyroid cancer and advanced renal cell carcinoma. Although this drug is increasingly used in therapy, its metabolism and effects on the organism are still not described in detail. Using the rat as an experimental animal model, this study aimed to investigate the metabolism of lenvatinib by rat microsomal enzymes and cytochrome P450 (CYPs) enzymes recombinantly expressed in SupersomesTMin vitro and to assess the effect of lenvatinib on rat CYP expression in vivo. Two metabolites, O-desmethyl lenvatinib, and lenvatinib N-oxide, were produced by rat CYPs in vitro. CYP2A1 and 2C12 were found to be the most effective in forming O-desmethyl lenvatinib, while CYP3A2 was found to primarily form lenvatinib N-oxide. The administration of lenvatinib to rats caused changes in the expression of mRNA and protein, as well as the activity of various CYPs, particularly in an increase in CYP1A1. Thus, the administration of lenvatinib to rats has an impact on the level of CYPs.
- MeSH
- chinoliny * farmakologie MeSH
- fenylmočovinové sloučeniny * farmakologie MeSH
- inhibitory proteinkinas * farmakologie MeSH
- inhibitory tyrosinkinasy MeSH
- jaterní mikrozomy účinky léků MeSH
- játra * účinky léků metabolismus MeSH
- krysa rodu rattus MeSH
- messenger RNA metabolismus genetika MeSH
- oxidace-redukce * účinky léků MeSH
- potkani Sprague-Dawley MeSH
- systém (enzymů) cytochromů P-450 * metabolismus MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Background and Objectives: Liver injury is a rare complication of cardiopulmonary resuscitation. Correct and early diagnosis and treatment are essential. The clinical signs of injury may be masked by the cardiac arrest. We present a single-centre retrospective observational study of traumatic liver injury after cardiopulmonary resuscitation. Materials and Methods: A retrospective analysis of the patients treated for liver injury after cardiopulmonary resuscitation was conducted. Demographic data, the cause of resuscitation, the duration of restoration of spontaneous circulation (ROSC), and the surgical approach were analysed. Results: We have treated nine patients with severe liver injury after cardiopulmonary resuscitation. The diagnosis was made on the basis of cardiopulmonary instability, a fall in the erythrocyte count in eight cases, and was confirmed by CT or ultrasound examination. The last one was diagnosed accidentally on MR. Surgery, in cases of unstable patients, was followed immediately after a diagnosis. We combined liver sutures and intra-abdominal packing with a planned second-look surgery. Five of the nine patients survived. Conclusions: Liver injury after cardiopulmonary resuscitation is rare and is associated with high mortality. The recurrence of cardiopulmonary instability and/or a low or falling red blood cell count are the main signs of this injury. Bedside ultrasound and CT scans are the most important methods to confirm the diagnosis. The rule of surgical repair is the same as in all liver injuries, regardless of aetiology. The key factors for survival include early diagnosis, together with the length of restoration of spontaneous circulation (ROSC).
- MeSH
- dospělí MeSH
- játra * zranění diagnostické zobrazování MeSH
- kardiopulmonální resuscitace * škodlivé účinky MeSH
- lidé středního věku MeSH
- lidé MeSH
- retrospektivní studie MeSH
- senioři MeSH
- srdeční zástava etiologie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- pozorovací studie MeSH
Phosphofructokinase-1 (PFK1) catalyzes the rate-limiting step of glycolysis, committing glucose to conversion into cellular energy. PFK1 is highly regulated to respond to the changing energy needs of the cell. In bacteria, the structural basis of PFK1 regulation is a textbook example of allostery; molecular signals of low and high cellular energy promote transition between an active R-state and inactive T-state conformation, respectively. Little is known, however, about the structural basis for regulation of eukaryotic PFK1. Here, we determine structures of the human liver isoform of PFK1 (PFKL) in the R- and T-state by cryoEM, providing insight into eukaryotic PFK1 allosteric regulatory mechanisms. The T-state structure reveals conformational differences between the bacterial and eukaryotic enzyme, the mechanisms of allosteric inhibition by ATP binding at multiple sites, and an autoinhibitory role of the C-terminus in stabilizing the T-state. We also determine structures of PFKL filaments that define the mechanism of higher-order assembly and demonstrate that these structures are necessary for higher-order assembly of PFKL in cells.
- MeSH
- adenosintrifosfát * metabolismus MeSH
- alosterická regulace MeSH
- elektronová kryomikroskopie MeSH
- fosfofruktokinasa-1 * metabolismus chemie genetika MeSH
- glykolýza MeSH
- játra enzymologie metabolismus MeSH
- konformace proteinů MeSH
- lidé MeSH
- molekulární modely MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Mitochondrial oxidative phosphorylation (OXPHOS) fuels cellular ATP demands. OXPHOS defects lead to severe human disorders with unexplained tissue specific pathologies. Mitochondrial gene expression is essential for OXPHOS biogenesis since core subunits of the complexes are mitochondrial-encoded. COX14 is required for translation of COX1, the central mitochondrial-encoded subunit of complex IV. Here we describe a COX14 mutant mouse corresponding to a patient with complex IV deficiency. COX14M19I mice display broad tissue-specific pathologies. A hallmark phenotype is severe liver inflammation linked to release of mitochondrial RNA into the cytosol sensed by RIG-1 pathway. We find that mitochondrial RNA release is triggered by increased reactive oxygen species production in the deficiency of complex IV. Additionally, we describe a COA3Y72C mouse, affected in an assembly factor that cooperates with COX14 in early COX1 biogenesis, which displays a similar yet milder inflammatory phenotype. Our study provides insight into a link between defective mitochondrial gene expression and tissue-specific inflammation.
- MeSH
- cyklooxygenasa 1 * MeSH
- DEAD box protein 58 MeSH
- DEAD-box RNA-helikasy metabolismus genetika MeSH
- játra * metabolismus patologie MeSH
- lidé MeSH
- membránové proteiny MeSH
- mitochondriální proteiny metabolismus genetika MeSH
- mitochondrie metabolismus MeSH
- mutace MeSH
- myši inbrední C57BL MeSH
- myši MeSH
- oxidativní fosforylace * MeSH
- proteosyntéza MeSH
- reaktivní formy kyslíku * metabolismus MeSH
- respirační komplex IV * metabolismus genetika MeSH
- RNA mitochondriální genetika metabolismus MeSH
- zánět * metabolismus genetika patologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
