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

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

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

BACKGROUND: Early identification of those with NAFLD activity score ≥ 4 and significant fibrosis (≥F2) or at-risk metabolic dysfunction-associated steatohepatitis (MASH) is a priority as these patients are at increased risk for disease progression and may benefit from therapies. We developed and validated a highly specific metabolomics-driven score to identify at-risk MASH. METHODS: We included derivation (n = 790) and validation (n = 565) cohorts from international tertiary centers. Patients underwent laboratory assessment and liver biopsy for metabolic dysfunction-associated steatotic liver disease. Based on 12 lipids, body mass index, aspartate aminotransferase, and alanine aminotransferase, the MASEF score was developed to identify at-risk MASH and compared to the FibroScan-AST (FAST) score. We further compared the performance of a FIB-4 + MASEF algorithm to that of FIB-4 + liver stiffness measurements (LSM) by vibration-controlled transient elastography (VCTE). RESULTS: The diagnostic performance of the MASEF score showed an area under the receiver-operating characteristic curve, sensitivity, specificity, and positive and negative predictive values of 0.76 (95% CI 0.72-0.79), 0.69, 0.74, 0.53, and 0.85 in the derivation cohort, and 0.79 (95% CI 0.75-0.83), 0.78, 0.65, 0.48, and 0.88 in the validation cohort, while FibroScan-AST performance in the validation cohort was 0.74 (95% CI 0.68-0.79; p = 0.064), 0.58, 0.79, 0.67, and 0.73, respectively. FIB-4+MASEF showed similar overall performance compared with FIB-4 + LSM by VCTE ( p = 0.69) to identify at-risk MASH. CONCLUSION: MASEF is a promising diagnostic tool for the assessment of at-risk MASH. It could be used alternatively to LSM by VCTE in the algorithm that is currently recommended by several guidance publications.

• MeSH
• biopsie škodlivé účinky   MeSH
• elastografie * MeSH
• fibróza MeSH
• jaterní cirhóza patologie   MeSH
• játra diagnostické zobrazování   patologie   MeSH
• lidé MeSH
• nealkoholová steatóza jater * patologie   MeSH
• prediktivní hodnota testů MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

BACKGROUND AND AIMS: Alpha-1 antitrypsin deficiency is an inherited disorder caused by alpha-1 antitrypsin (AAT) mutations. We analysed the association between alcohol intake and liver-related parameters in individuals with the heterozygous/homozygous Pi*Z AAT variant (Pi*MZ/Pi*ZZ genotype) found in the United Kingdom Biobank and the European Alpha1 liver consortium. METHODS: Reported alcohol consumption was evaluated in two cohorts: (i) the community-based United Kingdom Biobank (17 145 Pi*MZ, 141 Pi*ZZ subjects, and 425 002 non-carriers [Pi*MM]); and (ii) the European Alpha1 liver consortium (561 Pi*ZZ individuals). Cohort (ii) included measurements of carbohydrate-deficient transferrin (CDT). RESULTS: In both cohorts, no/low alcohol intake was reported by >80% of individuals, while harmful consumption was rare (~1%). Among Pi*MM and Pi*MZ individuals from cohort (i), moderate alcohol consumption resulted in a <30% increased rate of elevated transaminases and ~50% increase in elevated gamma-glutamyl transferase values, while harmful alcohol intake led to an at least twofold increase in the abnormal levels. In Pi*ZZ individuals from both cohorts, moderate alcohol consumption had no marked impact on serum transaminase levels. Among Pi*ZZ subjects from cohort (ii) who reported no/low alcohol consumption, those with increased CDT levels more often had signs of advanced liver disease. CONCLUSIONS: Pi*MZ/Pi*ZZ genotype does not seem to markedly aggravate the hepatic toxicity of moderate alcohol consumption. CDT values might be helpful to detect alcohol consumption in those with advanced fibrosis. More data are needed to evaluate the impact of harmful alcohol consumption.

• MeSH
• alfa-1-antitrypsin * genetika   krev   MeSH
• deficit alfa1-antitrypsinu * genetika   krev   diagnóza   komplikace   MeSH
• dospělí MeSH
• fenotyp * MeSH
• gama-glutamyltransferasa krev   MeSH
• genotyp MeSH
• játra patologie   MeSH
• kohortové studie MeSH
• lidé středního věku MeSH
• lidé MeSH
• pití alkoholu * škodlivé účinky   MeSH
• senioři MeSH
• transferin * analýza   metabolismus   analogy a deriváty   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Evropa MeSH
• Spojené království MeSH

Liver fibrosis is characterized by the activation of perivascular hepatic stellate cells (HSCs), the release of fibrogenic nanosized extracellular vesicles (EVs), and increased HSC glycolysis. Nevertheless, how glycolysis in HSCs coordinates fibrosis amplification through tissue zone-specific pathways remains elusive. Here, we demonstrate that HSC-specific genetic inhibition of glycolysis reduced liver fibrosis. Moreover, spatial transcriptomics revealed a fibrosis-mediated up-regulation of EV-related pathways in the liver pericentral zone, which was abrogated by glycolysis genetic inhibition. Mechanistically, glycolysis in HSCs up-regulated the expression of EV-related genes such as Ras-related protein Rab-31 (RAB31) by enhancing histone 3 lysine 9 acetylation on the promoter region, which increased EV release. Functionally, these glycolysis-dependent EVs increased fibrotic gene expression in recipient HSC. Furthermore, EVs derived from glycolysis-deficient mice abrogated liver fibrosis amplification in contrast to glycolysis-competent mouse EVs. In summary, glycolysis in HSCs amplifies liver fibrosis by promoting fibrogenic EV release in the hepatic pericentral zone, which represents a potential therapeutic target.

• MeSH
• extracelulární vezikuly * metabolismus   MeSH
• glykolýza * MeSH
• jaterní cirhóza * metabolismus   patologie   genetika   MeSH
• jaterní hvězdicovité buňky * metabolismus   patologie   MeSH
• játra metabolismus   patologie   MeSH
• lidé MeSH
• modely nemocí na zvířatech MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• Rab proteiny vázající GTP metabolismus   genetika   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

A combination of liver and heart dysfunction worsens the prognosis of human survival. The aim of this study was to investigate whether empagliflozin (a sodium-glucose transporter-2 inhibitor) has beneficial effects not only on cardiac and renal function but also on hepatic function. Adult (6-month-old) male spontaneously hypertensive rats (SHR) were fed a high-fat diet (60% fat) for four months to induce hepatic steatosis and mild heart failure. For the last two months, the rats were treated with empagliflozin (empa, 10 mg.kg-1.day-1 in the drinking water). Renal function and oral glucose tolerance test were analyzed in control (n=8), high-fat diet (SHR+HF, n=10), and empagliflozin-treated (SHR+HF+empa, n=9) SHR throughout the study. Metabolic parameters and echocardiography were evaluated at the end of the experiment. High-fat diet feeding increased body weight and visceral adiposity, liver triglyceride and cholesterol concentrations, and worsened glucose tolerance. Although the high-fat diet did not affect renal function, it significantly worsened cardiac function in a subset of SHR rats. Empagliflozin reduced body weight gain but not visceral fat deposition. It also improved glucose sensitivity and several metabolic parameters (plasma insulin, uric acid, and HDL cholesterol). In the liver, empagliflozin reduced ectopic lipid accumulation, lipoperoxidation, inflammation and pro-inflammatory HETEs, while increasing anti-inflammatory EETs. In addition, empagliflozin improved cardiac function (systolic, diastolic and pumping) independent of blood pressure. The results of our study suggest that hepatoprotection plays a decisive role in the beneficial effects of empagliflozin in preventing the progression of cardiac dysfunction induced by high-fat diet feeding.

• MeSH
• benzhydrylové sloučeniny * farmakologie   MeSH
• dieta s vysokým obsahem tuků * škodlivé účinky   MeSH
• glifloziny * farmakologie   MeSH
• glukosidy * farmakologie   MeSH
• hypertenze farmakoterapie   MeSH
• játra * účinky léků   metabolismus   patologie   MeSH
• kardiotonika farmakologie   MeSH
• krevní glukóza metabolismus   účinky léků   MeSH
• krevní tlak účinky léků   MeSH
• krysa rodu rattus MeSH
• ledviny účinky léků   metabolismus   patologie   MeSH
• ochranné látky farmakologie   MeSH
• potkani inbrední SHR * MeSH
• ztučnělá játra prevence a kontrola   farmakoterapie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Estrogeny jsou klíčové hormony, které hrají zásadní roli ve fyziologii reprodukčního systému u žen. Jejich terapeutické využití v hormonální léčbě, antikoncepci a léčbě hormonálně závislých onemocnění však může být spojeno s řadou nežádoucích účinků, zejména na játra. Tento článek se zaměřuje na mechanizmy působení estrogenů a jejich potenciální hepatotoxické účinky, stejně jako na rizikové faktory a možné rozdíly mezi jednotlivými představiteli.

Estrogens are key hormones that play a vital role in the physiology of the reproductive system in women. However, their therapeutic use in hormonal treatment, contraception, and the treatment of hormone-dependent diseases may be associated with a number of side effects, especially on the liver. This article focuses on the mechanisms of action of estrogens and their potential hepatotoxic effects, as well as risk factors and possible differences between representatives.

• MeSH
• estetrol farmakologie   metabolismus   škodlivé účinky   MeSH
• estradiol farmakologie   metabolismus   škodlivé účinky   MeSH
• estrogeny * farmakologie   metabolismus   škodlivé účinky   MeSH
• ethinylestradiol farmakologie   metabolismus   škodlivé účinky   MeSH
• játra * metabolismus   patologie   účinky léků   MeSH
• lékové interakce fyziologie   MeSH
• lékové postižení jater etiologie   metabolismus   MeSH
• lidé MeSH
• Check Tag
• lidé MeSH

Once absorbed through lung tissues, smog-soluble substances are readily distributable throughout organ system reaching approximately all cells perturbing the subcellular events at mitochondrial level. The present study aimed to detect the deleterious impact of smog-containing materials on mitochondrial and thereby serum pyruvate/lactate levels coincidentally with liver proper functionality. To do so, chronic smokers were recruited and sub-classified into groups based on chronicity of smoking; control (never smoked), G1=smokers for up to 5 years, G2=smokers for up to 10 years, and G3=smokers for up to 15 years. Serum samples were collected and stored for later on analysis. Results have confirmed that serum pyruvate/lactate and liver enzymes modulated reciprocally with smoking compared to control. The results also confirmed that liver enzymes were strongly modulated, GOT elevated while GPT reduced in a way reciprocal to chronicity, while ALP elevated in first few years of smoking in G1 group compared to other groups or control group. Serum albumin was significantly elevated in studied groups compared to control group with no changes appeared in total plasma protein and the bilirubin levels were higher in G2 group compared to G1 or G3 or control groups. Serum lactate and to certain extent serum pyruvate were also significantly perturbed showing higher levels in smokers compared to control or junior smokers. In conclusion, mitochondrial subcellular machinery are strongly affected following smoking indicated by serum pyruvate/lactate measurement and this in turn strongly affect liver functionality as an important organ involved in pyruvate-lactate demarcation and pertaining to the liver functionality indicated by bilirubin and total plasma protein or albumin measurements.

• MeSH
• dospělí MeSH
• játra * enzymologie   patologie   účinky léků   MeSH
• kouření * krev   patologie   škodlivé účinky   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mitochondrie patologie   účinky léků   MeSH
• mladý dospělý MeSH
• sérum chemie   enzymologie   účinky léků   MeSH
• statistika jako téma MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• Publikační typ
• klinická studie MeSH

BACKGROUND AND AIMS: Schistosoma mansoni infection is one of the worldwide leading causes of liver fibrosis and portal hypertension. The objective of this study was to evaluate whether polyhydroxylated bile acids (BAs), known to protect mice from the development of acquired cholestatic liver injury, counteract S. mansoni-induced inflammation and fibrosis. METHODS: Adult FVB/N wild type (WT) and Abcb11/Bsep-/- mice were infected with either 25 or 50 S. mansoni cercariae. Eight weeks post infection, effects on liver histology, serum biochemistry, gene expression profile of proinflammatory cytokines and fibrotic markers, hepatic hydroxyproline content and FACS analysis were performed. RESULTS: Bsep-/- mice infected with S. mansoni showed significantly less hepatic inflammation and tendentially less fibrosis compared to infected WT mice. Despite elevated alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase levels in infected Bsep-/- mice, inflammatory cells such as M2 macrophages and Mac-2/galectin-3+ cells were reduced in these animals. Accordingly, mRNA-expression levels of anti-inflammatory cytokines (IL-4 and IL-13) were increased in Bsep-/- mice upon infection. Furthermore, infected Bsep-/- mice exhibited decreased hepatic egg load and parasite fecundity, consequently affecting the worm reproduction rate. This outcome could arise from elevated serum BA levels and lower blood pH in Bsep-/- mice. CONCLUSIONS: The loss of Bsep and the resulting changes in bile acid composition and blood pH are associated with the reduction of parasite fecundity, thus attenuating the development of S. mansoni-induced hepatic inflammation and fibrosis.

• MeSH
• cytokiny metabolismus   MeSH
• fertilita MeSH
• jaterní cirhóza prevence a kontrola   etiologie   MeSH
• játra patologie   MeSH
• myši MeSH
• paraziti * MeSH
• Schistosoma mansoni MeSH
• schistosomiasis mansoni * komplikace   MeSH
• zánět patologie   MeSH
• žlučové kyseliny a soli metabolismus   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH