BACKGROUND: A number of recent studies have shown that the intestinal microbiome, part of the brain-gut axis, is implicated in the pathophysiology of multiple sclerosis. An essential part of this axis, is the intestinal barrier and gastrointestinal disorders with intestinal barrier dysregulation appear to be linked to CNS demyelination, and hence involved in the etiopathogenesis of multiple sclerosis (MS). OBJECTIVE: The aim of this study was to evaluate the integrity of the intestinal barrier in patients with clinically definite multiple sclerosis (CDMS) and clinically isolated syndrome (CIS) using two serum biomarkers, claudin-3 (CLDN3), a component of tight epithelial junctions, and intestinal fatty acid binding protein (I-FABP), a cytosolic protein in enterocytes. METHODS: Serum levels of CLDN3 in 37 MS patients and 22 controls, and serum levels of I-FABP in 46 MS patients and 51 controls were measured using commercial ELISA kits. Complete laboratory tests excluded the presence of gluten-related disorders in all subjects. Thirty MS patients received either disease-modifying drugs (DMD), immunosuppression (IS) or corticosteroid treatment. RESULTS: CLDN3 levels were only significantly higher in the MS patients treated with DMD or IS compared to the control group (P=0.006). There were no differences in I-FABP serum levels between the groups. Serum CLDN3 levels did not correlate with serum I-FABP levels in CDMS, in CIS patients or controls. CONCLUSIONS: In multiple sclerosis patients, the intestinal epithelium may be impaired with increased permeability, but without significant enterocyte damage characterized by intracellular protein leakage. Based on our data, CLDN3 serum levels appear to assess intestinal dysfunction in MS patients but mainly in treated ones.
- MeSH
- Biomarkers * blood MeSH
- Claudin-3 * metabolism MeSH
- Adult MeSH
- Intestinal Barrier Function MeSH
- Middle Aged MeSH
- Humans MeSH
- Permeability * MeSH
- Fatty Acid-Binding Proteins * blood MeSH
- Multiple Sclerosis * physiopathology metabolism blood MeSH
- Intestinal Mucosa metabolism MeSH
- Case-Control Studies MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Keywords
- studie Lipidica, lipidotomický test,
- MeSH
- Early Detection of Cancer methods MeSH
- Hematologic Tests MeSH
- Clinical Studies as Topic MeSH
- Plasma MeSH
- Humans MeSH
- Lipids blood MeSH
- Multicenter Studies as Topic MeSH
- Biomarkers, Tumor MeSH
- Pancreatic Neoplasms * diagnosis prevention & control MeSH
- Primary Health Care MeSH
- Check Tag
- Humans MeSH
The abnormalities in blood coagulation in patients with diabetes can lead to a prothrombotic state and requirement for the administration of direct anticoagulants. However, no comparative studies have been conducted on the effects of different direct anticoagulants. A head-to-head investigation of the impact of anticoagulants in 50 patients of type 1 diabetes mellitus (DMT1) was performed, and the data were compared to 50 generally healthy individuals. Prothrombin time (PT) and activated partial thromboplastin time (aPTT) were measured in plasma treated with vehicle, heparin, or four direct anticoagulants at 1 μM. In addition to common biochemical parameters, novel inflammatory markers (neopterin, kynurenine/tryptophan ratio) and major vitamin K forms were measured. Heparin and dabigatran treatments resulted in prolonged coagulation in DMT1 patients compared to healthy individuals in both tests (both p < 0.001). The same phenomenon was observed for rivaroxaban and apixaban-treated samples in PT (p < 0.001). Interestingly, healthy volunteers had higher total vitamin K levels than DMT1. Further analysis suggested that observed coagulation differences were not caused by differences in glycemia but were rather associated with an unexpected, better lipid profile of our DMT1 group. There were also correlations between prolongation of coagulation brought about by the most active anticoagulants and inflammatory markers, and hence inflammatory state probably also contributed to the differences, as well as the mentioned differences in vitamin K levels. Conclusively, this paper suggests the suitability for controlling the effects of direct anticoagulants in DMT1 patients.
- MeSH
- Anticoagulants * pharmacology therapeutic use MeSH
- Dabigatran pharmacology MeSH
- Diabetes Mellitus, Type 1 * blood drug therapy MeSH
- Adult MeSH
- Blood Coagulation drug effects MeSH
- Heparin pharmacology MeSH
- Middle Aged MeSH
- Humans MeSH
- Young Adult MeSH
- Partial Thromboplastin Time MeSH
- Prothrombin Time MeSH
- Rivaroxaban pharmacology MeSH
- Case-Control Studies MeSH
- Vitamin K * blood MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Young Adult MeSH
- Male MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
Cíl: Vztah mezi hypercholesterolemií, zvláště zvýšenými hodnotami cholesterolu v lipoproteinech o nízké hustotě (lDl-c) a ischemickou chorobou srdeční (ichS), je potvrzen důkazy z předchozích epidemiologic kých studií. Důležité bylo popsání souvislosti mezi genetickým polymorfismem a hodnotami lipidů v plazmě. cílem této studie bylo zkoumat vztah mezi variantami rs5918 t>c genu pro itGB3 a variantou rs1799837 c>t ge nu pro APo-A1 na jedné straně a metabolismem lipidů v séru na straně druhé. Pacienti a metody: Do této studie bylo zařazeno celkem 100 jedinců s ichS a 250 zdravých jedinců. u každé ho účastníka bylo provedeno základní biochemické vyšetření včetně stanovení koncentrace glukózy v séru, celkového cholesterolu (total cholesterol, tc) v séru, hodnot hDl-c, lDl-c a triglyceridů. Pro genotypizaci polymorfismů genů pro itGB3 a APo-A1 byla použita polymerázová řetězová reakce s následnou analýzou polymorfismu délky restrikčních fragmentů (restriction fragment length polymorphism, rflP). Výsledky: Pokud se týče genotypu a distribuce alel polymorfismu rs5918 t>c genu pro itGB3, vyskytovala se alela c častěji ve skupině s ichS než v kontrolní skupině (p = 0,001). Ve skupině s ichS byla navíc pozorována statisticky významná souvislost mezi genotypem rs5918 itGB3 a hodnotami celkového cholesterolu v geno typu cc na jedné straně a tc v séru a cholesterolu v lipoproteinech o vysoké hustotě (hDl-c) (p = 0,0006, resp. p = 0,016). nicméně ani v kontrolní skupině, ani ve skupině s ichS nebyla nalezena statisticky významná spojitost mezi polymorfismem rs1799837 c>t genu pro APo-A1 a biochemickými parametry. Závěr: Výsledky prokázaly, že varianta rs5918 t>c genu pro itGB3 by mohla být z klinického hlediska vý znamná jako genetický marker zvýšené vnímavosti k rozvoji ichS. Alelu c varianty rs5918 genu pro itGB3 by tak bylo možno navrhnout pro screening potenciálního rozvoje ichS u populace kyperských turků, kteří se dostaví na kontrolu k lékaři.
Aim: The relationship between hypercholesterolemia, particularly elevated low density lipoprotein-cholesterol (LDL-C) levels and coronary artery disease is recognized by the evidence from previous epidemiologic studies. Importantly, genetic polymorphisms on different genes have been reported to be associated with plasma lipid levels. In this particular study, we aimed to investigate the relationship between the ITGB3 gene rs5918 T>C and APO-A1 gene rs1799837 C>T markers and serum lipid metabolism. Patients and methods: A total of 100 subjects with CAD and 250 healthy subjects were involved in the current study. A basic biochemical analysis, including serum glucose, total serum cholesterol, HDL-C, LDL-C and triglycerides, was performed for each participant. Genotyping for the ITGB3 gene and APO-A1 gene polymorphisms was performed by polymerase chain reaction followed by restriction fragment length polymorphism (RFLP) analysis. Results: With respect to the genotype and allele distributions of ITGB3 rs5918 T>C polymorphism, the frequency of the C allele was higher in the coronary artery disease (CAD) group compared to the control group (p = 0.001). Moreover, there was a statistically significant association detected between ITGB3 rs5918 CC genotype and serum total cholesterol (TC) and high-density lipoprotein cholesterol (HDL-C) (p = 0.0006, p = 0.016, respectively) in CAD group. However there was no statistically significant association was identified between the APOA1 rs1799837 C>T polymorphism and biochemical parameters in control and CAD group. Conclusion: The results demonstrated that rs5918 T>C variant within the ITGB3 gene might have a clinical importance as a genetic marker which increases the susceptibility to CAD. Therefore, the ITGB3 gene rs5918 C allele may be offered as a screening option for CAD in Turkish Cypriot population who come in for medical check-up.
Background: Statin intolerance is a serious therapeutic dilemma in secondary cardiovascular prevention (e.g., ESC/EAS Guidelines 2023). This is especially true when confirmed by genetic predisposition and complicated by rhabdomyolysis. Although several non-statin agents have become available in recent years, evidence regarding their combined use in high-risk statin-intolerant patients remains limited. Furthermore, the pharmacokinetics of statins in toxic concentrations are poorly characterized in clinical settings. Case Presentation: We present two cases of genetically confirmed statin-induced rhabdomyolysis, both accompanied by severe acute kidney injury requiring renal replacement therapy. In both patients, serial measurements of rosuvastatin plasma concentrations revealed markedly delayed elimination, with detectable levels persisting for several weeks despite ongoing dialysis. Estimated half-lives exceeded 7 days in both cases, far beyond the known therapeutic range. Genetic testing identified SLCO1B1, ABCB1, and CYP2C9 polymorphisms linked to reduced hepatic uptake and impaired drug clearance. Following biochemical recovery, both patients were initiated on a triple non-statin lipid-lowering regimen consisting of ezetimibe, bempedoic acid, and inclisiran. The combination was well tolerated, with no recurrence of muscle-related symptoms or biochemical toxicity. LDL-C levels were reduced from 3.05 to 1.59 mmol/L and from 4.99 to 1.52 mmol/L, respectively, with sustained response over 12 and 40 weeks. Full lipid profiles demonstrated favorable changes across all parameters. Conclusions: These two cases suggest that the combination of ezetimibe, inclisiran, and bempedoic acid may serve as a safe and effective therapeutic option in patients with severe statin intolerance. Pharmacogenetic testing and serial pharmacokinetic assessment may guide personalized lipid-lowering strategies and improve outcomes in this challenging patient population.
- Publication type
- Journal Article MeSH
- Case Reports MeSH
Integral membrane proteins carry out essential functions in the cell, and their activities are often modulated by specific protein-lipid interactions in the membrane. Here, we elucidate the intricate role of cardiolipin (CDL), a regulatory lipid, as a stabilizer of membrane proteins and their complexes. Using the in silico-designed model protein TMHC4_R (ROCKET) as a scaffold, we employ a combination of molecular dynamics simulations and native mass spectrometry to explore the protein features that facilitate preferential lipid interactions and mediate stabilization. We find that the spatial arrangement of positively charged residues as well as local conformational flexibility are factors that distinguish stabilizing from non-stabilizing CDL interactions. However, we also find that even in this controlled, artificial system, a clear-cut distinction between binding and stabilization is difficult to attain, revealing that overlapping lipid contacts can partially compensate for the effects of binding site mutations. Extending our insights to naturally occurring proteins, we identify a stabilizing CDL site within the E. coli rhomboid intramembrane protease GlpG and uncover its regulatory influence on enzyme substrate preference. In this work, we establish a framework for engineering functional lipid interactions, paving the way for the design of proteins with membrane-specific properties or functions.
- MeSH
- DNA-Binding Proteins MeSH
- Endopeptidases metabolism chemistry genetics MeSH
- Escherichia coli metabolism genetics MeSH
- Cardiolipins * metabolism chemistry MeSH
- Membrane Proteins * metabolism chemistry genetics MeSH
- Protein Engineering * MeSH
- Escherichia coli Proteins * metabolism chemistry genetics MeSH
- Molecular Dynamics Simulation MeSH
- Protein Binding MeSH
- Publication type
- Journal Article MeSH
The aim of the study was to analyze the variables that modify the levels of oxidative DNA damage and lipid peroxidation in non-smoking mothers and their newborns from environmentally distinct localities of the Czech Republic: Ceske Budejovice (CB, an agricultural region) and Karvina (an industrial region). Personal, socio-economic and medical data, concentrations of particulate matter of aerodynamic diameter < 2.5 μm (PM2.5) and benzo[a]pyrene (B[a]P) in the ambient air, the activities of antioxidant mechanisms (superoxide dismutase, catalase, glutathione peroxidase) and antioxidant capacity), the levels of pro-inflammatory cytokines, the concentrations of persistent organic pollutants (POPs) in blood plasma/cord blood plasma and urinary levels of polycyclic aromatic hydrocarbons metabolites (OH-PAHs) were investigated as parameters potentially affecting the markers of DNA oxidation (8-oxo-7,8-dihydro-2'-deoxyguanosine, 8-oxodG) and lipid peroxidation (15-F2t-isoprostane, 15-F2t-IsoP). Significantly higher levels of POPs were detected in the plasma of mothers/newborns from CB (p < 0.001), while increased external levels of B[a]P and PM2.5, confirmed by analyzing urinary OH-PAHs, were found in Karvina subjects (p < 0.001). In mothers, multivariate analysis showed no significant difference in oxidative stress markers (15-F2t-IsoP, 8-oxodG) between the two localities. The analysis further revealed that neither in CB nor, unexpectedly, in Karvina, did PAH exposure affect maternal lipid peroxidation. Significant associations between OH-PAHs and 15-F2t-IsoP or 8-oxodG were observed only in newborns. In addition, multivariate analyses revealed a borderline significant association between locality and 8-oxodG in the urine of all newborns (p = 0.05). In conclusion, not only the maternal exposure of PAHs but also some POPs can negatively affect oxidative stress status in the early-life of newborns.
- Publication type
- Journal Article MeSH
Accumulating evidence suggests that manganese oxide nanoparticles (NPs) show multiple enzyme-mimicking antioxidant activities, which supports their potential in redox-targeting therapeutic strategies for diseases with impaired redox signaling. However, the systemic administration of any NP requires thorough hemocompatibility testing. In this study, we assessed the hemocompatibility of synthesized Mn3O4 NPs, identifying their ability to induce spontaneous hemolysis and eryptosis or impair osmotic fragility. Concentrations of up to 20 mg/L were found to be safe for erythrocytes. Eryptosis assays were shown to be more sensitive than hemolysis and osmotic fragility as markers of hemocompatibility for Mn3O4 NP testing. Flow cytometry- and confocal microscopy-based studies revealed that eryptosis induced by Mn3O4 NPs was accompanied by Ca2+ overload, altered redox homeostasis verified by enhanced intracellular reactive oxygen species (ROS) and reactive nitrogen species (RNS), and a decrease in the lipid order of cell membranes. Furthermore, Mn3O4 NP-induced eryptosis was calpain- and caspase-dependent.
- MeSH
- Cell Membrane * metabolism drug effects MeSH
- Eryptosis * drug effects MeSH
- Erythrocytes drug effects metabolism MeSH
- Hemolysis drug effects MeSH
- Calpain * metabolism MeSH
- Caspases * metabolism MeSH
- Humans MeSH
- Nanoparticles * chemistry MeSH
- Oxides * pharmacology chemistry MeSH
- Reactive Nitrogen Species * metabolism MeSH
- Reactive Oxygen Species * metabolism MeSH
- Manganese Compounds * pharmacology chemistry MeSH
- Calcium * metabolism MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
Limited knowledge exists on persistent organic pollutants (POPs), including polychlorinated biphenyls (PCBs) and organochlorine pesticides (OCPs), in mother-child pairs from Northern Finland. This study examines plasma PCB and OCP concentrations and their determinants. Blood plasma concentrations of 13 PCBs and 6 OCPs were measured in mothers and in cord samples from the NUGEN birth cohort (N = 102, 2012-2014). Correlations between maternal and cord POPs were assessed using Spearman correlation, and linear regression identified factors influencing lipid-adjusted POPs. Maternal age and alcohol consumption during pregnancy were positively associated with PCBs and OCPs. Pre-pregnancy BMI and weight change during pregnancy were inversely associated with PCBs, but positively with p,p'-DDE in children. Increasing parity and smoking were associated with lower PCBs. Maternal fish consumption was associated with higher PCBs in children. Finnish pregnant women had lower PCBs and OCPs than other European populations. These findings inform exposure risk assessment and prevention strategies.
- MeSH
- Hydrocarbons, Chlorinated * blood MeSH
- Child MeSH
- Adult MeSH
- Fetal Blood chemistry MeSH
- Cohort Studies MeSH
- Environmental Pollutants * blood MeSH
- Humans MeSH
- Maternal Exposure * MeSH
- Young Adult MeSH
- Infant, Newborn MeSH
- Pesticides * blood MeSH
- Polychlorinated Biphenyls * blood MeSH
- Pregnancy MeSH
- Prenatal Exposure Delayed Effects MeSH
- Check Tag
- Child MeSH
- Adult MeSH
- Humans MeSH
- Young Adult MeSH
- Male MeSH
- Infant, Newborn MeSH
- Pregnancy MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Geographicals
- Finland MeSH
Východiska: Hledání účinných biomarkerů pro včasnou diagnostiku ovariálního karcinomu (ovarian cancer – OC) patří k naléhavým úkolům moderní onkogynekologie. Metabolické profilování pomocí ultra vysokoúčinné kapalinové chromatografie a hmotnostní spektrometrie (ultraigh performance liquid chromatography and mass spectrometry – UHPLC-MS) poskytuje informace o souhrnu všech nízkomolekulárních metabolitů vzorku biologických tekutin pacienta, které odrážejí procesy probíhající v těle. Cílem studie bylo prozkoumat metabolomický profil krevní plazmy a moči pacientek se serózním ovariálním adenokarcinomem pomocí UHPLC-MS. Materiál a metody: K provedení metabolomické analýzy bylo odebráno 60 vzorků krevní plazmy a 60 vzorků moči pacientek s diagnózou serózního karcinomu vaječníků a 20 vzorků zdravých dobrovolníků. Chromatografická separace byla provedena na chromatografu Vanquish Flex UHPLC System (Thermo Scientific, Německo). Analýza hmotnostní spektrometrií byla provedena na Orbitrap Exploris 480 (Thermo Scientific, Německo) vybaveném elektrosprejovým ionizačním zdrojem. Bioinformatická analýza byla provedena pomocí Compound Discoverer Software (Thermo Fisher Scientific, USA), statistická analýza dat byla provedena v programovacím jazyce Python pomocí knihovny SciPy. Výsledky: Pomocí UHPLC-MS bylo v krevní plazmě identifikováno 1 049 metabolitů různých tříd. U pacientek s OC mělo 8 metabolitů významně nižší koncentraci (p < 0,01) ve srovnání se zdravými dárci, zatímco u 19 látek byly zjištěny vyšší hladiny (p < 0,01). Během metabolomického profilování vzorků moči bylo identifikováno 417 metabolitů: 12 látek mělo významně nižší koncentraci ve srovnání se zjevně zdravými jedinci a u 14 látek byly hladiny vyšší (p < 0,01). U pacientek se serózním adenokarcinomem vaječníků byla zjištěna významná změna v metabolomu krevní plazmy a moči, vyjádřená abnormálními koncentracemi lipidů a jejich derivátů, mastných kyselin a jejich derivátů, acylkarnitinů, fosfolipidů, aminokyselin a jejich derivátů, derivátů dusíkatých bází a steroidů. Mezi nejslibnější markery tohoto onemocnění přitom patří kynurenin, kyselina myristová, lysofosfatidylcholin a L-oktanoylkarnitin. Závěr: Odhalené změny v metabolomu se mohou stát základem pro zlepšení přístupů k diagnostice serózního ovariálního adenokarcinomu.
Background: The search for effective biomarkers for ovarian cancer (OC) early diagnosis is an urgent task of modern oncogynecology. Metabolic profiling by ultra-high performance liquid chromatography and mass spectrometry (UHPLC-MS) provides information on the totality of all low molecular weight metabolites of patient’s biological fluids sample, reflecting the processes occurring in the body. The aim of the study was to research blood plasma and urine metabolomic profile of patients with serous ovarian adenocarcinoma by UHPLC-MS. Material and methods: To perform metabolomic analysis, 60 blood plasma samples and 60 urine samples of patients diagnosed with serous ovarian carcinoma and 20 samples of apparently healthy volunteers were taken. Chromatographic separation was performed on a Vanquish Flex UHPLC System chromatograph (Thermo Scientific, Germany). Mass spectrometric analysis was performed on an Orbitrap Exploris 480 (Thermo Scientific, Germany) equipped with an electrospray ionization source. Bioinformatic analysis was performed using Compound Discoverer Software (Thermo Fisher Scientific, USA), statistical data analysis was performed in the Python programming language using the SciPy library. Results: Using UHPLC-MS, 1,049 metabolites of various classes were identified in blood plasma. In patients with OC, 8 metabolites had a significantly lower concentration (P < 0.01) compared with conditionally healthy donors, while the content of 19 compounds, on the contrary, increased (P < 0.01). During the metabolomic profiling of urine samples, 417 metabolites were identified: 12 compounds had a significantly lower concentration compared to apparently healthy individuals, the content of 14 compounds increased (P < 0.01). In patients with ovary serous adenocarcinoma, a significant change in the metabolome of blood plasma and urine was found, expressed in abnormal concentrations of lipids and their derivatives, fatty acids and their derivatives, acylcarnitines, phospholipids, amino acids and their derivatives, derivatives of nitrogenous bases and steroids. At the same time, kynurenine, myristic acid, lysophosphatidylcholine and L-octanoylcarnitine are the most promising markers of this disease. Conclusion: The revealed changes in the metabolome can become the basis for improving approaches to the diagnosis of serous ovarian adenocarcinoma.
