Browsing by Subject "HUMAN PLASMA"

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  • Nguyen, Su Duy; Javanainen, Matti; Rissanen, Sami; Zhao, Hongxia; Huusko, Jenni; Kivelä, Annukka M.; Ylä-Herttuala, Seppo; Navab, Mohamad; Fogelman, Alan M.; Vattulainen, Ilpo; Kovanen, Petri T.; Öörni, Katariina (2015)
    Lipolytic modification of LDL particles by SMase generates LDL aggregates with a strong affinity for human arterial proteoglycans and may so enhance LDL retention in the arterial wall. Here, we evaluated the effects of apoA-I mimetic peptide 4F on structural and functional properties of the SMase-modified LDL particles. LDL particles with and without 4F were incubated with SMase, after which their aggregation, structure, and proteoglycan binding were analyzed. At a molar ratio of L-4F to apoB-100 of 2.5 to 20: 1, 4F dose-dependently inhibited SMase-induced LDL aggregation. At a molar ratio of 20: 1, SMase-induced aggregation was fully blocked. Binding of 4F to LDL particles inhibited SMase-induced hydrolysis of LDL by 10% and prevented SMase-induced LDL aggregation. In addition, the binding of the SMase-modifi ed LDL particles to human aortic proteoglycans was dose-dependently inhibited by pretreating LDL with 4F. The 4F stabilized apoB-100 conformation and inhibited SMase-induced conformational changes of apoB-100. Molecular dynamic simulations showed that upon binding to protein-free LDL surface, 4F locally alters membrane order and fluidity and induces structural changes to the lipid layer. Collectively, 4F stabilizes LDL particles by preventing the SMase-induced conformational changes in apoB-100 and so blocks SMase-induced LDL aggregation and the resulting increase in LDL retention.
  • Kylli, Petri; Hankemeier, Thomas; Kostiainen, Risto (2017)
    Oxysterols are oxygenated cholesterols that are important in many cell functions and they may also be indicative of certain diseases. The purpose of this work was to study the feasibility of ultra-performance liquid chromatography-ion mobility-time-of-flight mass spectrometry (UPLC-IM-TOFMS) using traveling wave cell in analyzing oxysterols and especially their isomers in biological samples. Oxysterols were analyzed as their p-toluenesulfonyl isocyanate derivatives, which improved the separation of isomeric oxysterols by ion mobility and ionization efficiency in the electrospray ionization step. The UPLC-IM-TOFMS method was shown to be fast and to provide good quantitative performance. The feasibility of the method was demonstrated in the analyses of oxysterols in fibroblast cell samples. (C) 2017 Elsevier B.V. All rights reserved.
  • Kiamehr, Mostafa; Viiri, Leena E.; Vihervaara, Terhi; Koistinen, Kaisa M.; Hilvo, Mika; Ekroos, Kim; Kakela, Reijo; Aalto-Setala, Katriina (2017)
    Hepatocyte-like cells (HLCs) differentiated from human induced pluripotent stem cells (iPSCs) offer an alternative model to primary human hepatocytes to study lipid aberrations. However, the detailed lipid profile of HLCs is yet unknown. In the current study, functional HLCs were differentiated from iPSCs generated from dermal fibroblasts of three individuals by a three-step protocol through the definitive endoderm (DE) stage. In parallel, detailed lipidomic analyses as well as gene expression profiling of a set of lipid-metabolism-related genes were performed during the entire differentiation process from iPSCs to HLCs. Additionally, fatty acid (FA) composition of the cell culture media at different stages was determined. Our results show that major alterations in the molecular species of lipids occurring during DE and early hepatic differentiation stages mainly mirror the quality and quantity of the FAs supplied in culture medium at each stage. Polyunsaturated phospholipids and sphingolipids with a very long FA were produced in the cells at a later stage of differentiation. This work uncovers the previously unknown lipid composition of iPSC-HLCs and its alterations during the differentiation in conjunction with the expression of key lipid-associated genes. Together with biochemical, functional and gene expression measurements, the lipidomic analyses allowed us to improve our understanding of the concerted influence of the exogenous metabolite supply and cellular biosynthesis essential for iPSC-HLC differentiation and function. Importantly, the study describes in detail a cell model that can be applied in exploring, for example, the lipid metabolism involved in the development of fatty liver disease or atherosclerosis.
  • Lassenius, Mariann I.; Makinen, Ville-Petteri; Fogarty, Christopher; Peraneva, Lina; Jauhiainen, Matti; Pussinen, Pirkko J.; Taskinen, Marja-Riitta; Kirveskari, Juha; Vaarala, Outi; Nieminen, Janne K.; Horkko, Sohvi; Kangas, Antti J.; Soininen, Pasi; Ala-Korpela, Mika; Gordin, Daniel; Ahola, Aila J.; Forsblom, Carol; Groop, Per Henrik; Lehto, Markku; FinnDiane Study Grp (2014)
  • Pozharitskaya, Olga N.; Shikov, Alexander N.; Faustova, Natalya M.; Obluchinskaya, Ekaterina D.; Kosman, Vera M.; Vuorela, Heikki; Makarov, Valery G. (2018)
    Fucus vesiculosus L., known as bladderwrack, belongs to the brown seaweeds, which are widely distributed throughout northern Russia, Atlantic shores of Europe, the Baltic Sea, Greenland, the Azores, the Canary Islands, and shores of the Pacific Ocean. Fucoidan is a major fucose-rich sulfated polysaccharide found in Fucus (F.) vesiculosus. The pharmacokinetic profiling of active compounds is essential for drug development and approval. The aim of the study was to evaluate the pharmacokinetics and tissue distribution of fucoidan in rats after a single-dose oral administration. Fucoidan was isolated from F. vesiculosus. The method of measuring anti-activated factor X (anti-Xa) activity by amidolytic assay was used to analyze the plasma and tissue concentrations of fucoidan. The tissue distribution of fucoidan after intragastric administration to the rats was characterized, and it exhibited considerable heterogeneity. Fucoidan preferentially accumulates in the kidneys (AUC(0-t) = 10.74 mu g.h/g; C-max = 1.23 mu g/g after 5 h), spleen (AUC(0-t) = 6.89 mu g.h/g; C-max = 0.78 mu g/g after 3 h), and liver (AUC(0-t) = 3.26 mu g.h/g; C-max = 0.53 mu g/g after 2 h) and shows a relatively long absorption time and extended circulation in the blood, with a mean residence time (MRT) = 6.79 h. The outcome of this study provides additional scientific data for traditional use of fucoidan-containing plants and offers tangible support for the continued development of new effective pharmaceuticals using fucoidan.
  • Hallamaa, Raija; Batchu, Krishna (2016)
    Background: Lipids have become an important target for searching new biomarkers typical of different autoimmune and allergic diseases. The most common allergic dermatitis of the horse is related to stings of insects and is known as insect bite hypersensitivity (IBH) or summer eczema, referring to its recurrence during the summer months. This intense pruritus has certain similarities with atopic dermatitis of humans. The treatment of IBH is difficult and therefore new strategies for therapy are needed. Autoserum therapy based on the use of serum phospholipids has recently been introduced for horses. So far, serum lipids relating to these allergic disorders have been poorly determined. The main aim of this study was to analyse phospholipid profiles in the sera of horses with allergic dermatitis and in their healthy controls and to further assess whether these lipid profiles change according to the clinical status after therapy. Methods: Sera were collected from 10 horses with allergic dermatitis and from 10 matched healthy controls both before and 4 weeks after the therapy of the affected horses. Eczema horses were treated with an autogenous preparation made from a horse's own serum and used for oral medication. Samples were analysed for their phospholipid content by liquid chromatography coupled to a triple-quadrupole mass spectrometer (LC-MS). Data of phospholipid concentrations between the groups and over the time were analysed by using the Friedman test. Correlations between the change of concentrations and the clinical status were assessed by Spearman's rank correlation test. Results: The major phospholipid classes detected were phosphatidylcholine (PC), sphingomyelin (SM), phosphatidylinositol (PI) and phosphatidylethanolamine (PE). Eczema horses had significantly lower total concentrations of PC (p <0.0001) and SM (p = 0.0115) than their healthy controls. After a 4-week therapy, no significant differences were found between the groups. Changes in SM concentrations correlated significantly with alterations in clinical signs (p = 0.0047). Conclusions: Horses with allergic dermatitis have an altered phospholipid profile in their sera as compared with healthy horses and these profiles seem to change according to their clinical status. Sphingomyelin seems to have an active role in the course of equine insect bite hypersensitivity.
  • Ranta, Merja; Ketola, Raimo (2016)
    A liquid chromatography-tandem mass spectrometric (LC-MS/MS) method was developed and validated for the analysis of seven common sartans (candesartan, eprosartan, losartan, olmesartan, telmisartan, valsartan, and losartan carboxylic acid (EXP3174), the active metabolite of losartan) in postmortem blood samples with liquid-liquid extraction. Detection was accomplished by triple-quadrupole MS in the selected reaction monitoring mode. The validation procedure showed low limits of quantitation of 5 ng/mL for all compounds with good accuracy and precision. The matrix effect was evaluated from the variation of peak areas and concentrations. The method shows some matrix effect but the effect was efficiently compensated by using an internal standard method. The method was applied to the analysis of sartans in postmortem blood samples, and produced 534 positive findings during 2014-2015. Nine deaths were encountered where the concentration of a sartan was very high, indicating intoxication together with other causes of death or multi-drug intoxication. The quantitative results indicate that sartans do not show significant postmortem redistribution; thus concentrations higher than the therapeutic range can be considered as being toxic or fatal.
  • Ketola, Raimo A.; Ojanperä, Ilkka (2019)
    Concentration distributions for 183 drugs and metabolites frequently found in post-mortem (PM) femoral venous blood were statistically characterized based on an extensive database of 122 234 autopsy cases investigated during an 18-year period in a centralized laboratory. The cases represented all causes of death, with fatal drug poisonings accounting for 8%. The proportion of males was 74% with a median age of 58 years compared with 26% females with a median age of 64 years. In 36% of these cases, blood alcohol concentration was higher than or equal to 0.2 parts per thousand, the median being 1.6 parts per thousand. The mean, median, and upper percentile (90th, 95th, 97.5th) drug concentrations were established, as the median PM concentrations give an idea of the "normal" PM concentration level, and the upper percentile concentrations indicate possible overdose levels. A correspondence was found between subsets of the present and the previously published PM drug concentrations from another laboratory that grouped cases according to the cause of death. Our results add to the knowledge for evidence-based interpretation of drug-related deaths.
  • Tan, Karen Mei-Ling; Tint, Mya-Thway; Kothandaraman, Narasimhan; Michael, Navin; Sadananthan, Suresh Anand; Velan, S. Sendhil; Fortier, Marielle; Yap, Fabian; Tan, Kok Hian; Gluckman, Peter D.; Chong, Yap-Seng; Chong, Mary F. F.; Lee, Yung Seng; Godfrey, Keith M.; Eriksson, Johan G.; Cameron-Smith, David (2022)
    Context The kynurenine pathway generates metabolites integral to energy metabolism, neurotransmission, and immune function. Circulating kynurenine metabolites positively correlate with adiposity in children and adults, yet it is not known whether this relationship is present already at birth. Objective In this prospective longitudinal study, we investigate the relationship between cord blood kynurenine metabolites and measures of adiposity from birth to 4.5 years. Methods Liquid chromatography-tandem mass spectrometry was used to quantify cord blood kynurenine metabolites in 812 neonates from the Growing Up in Singapore Towards healthy Outcomes (GUSTO) study. Fat percentage was measured by air displacement plethysmography and abdominal adipose tissue compartment volumes; superficial (sSAT) and deep subcutaneous (dSAT) and internal adipose tissue were quantified by magnetic resonance imaging at early infancy in a smaller subset of neonates, and again at 4 to 4.5 years of age. Results Cord blood kynurenine metabolites appeared to be higher in female newborns, higher in Indian newborns compared with Chinese newborns, and higher in infants born by cesarean section compared with vaginal delivery. Kynurenine, xanthurenic acid, and quinolinic acid were positively associated with birthweight, but not with subsequent weight during infancy and childhood. Quinolinic acid was positively associated with sSAT at birth. Kynurenic acid and quinolinic acid were positively associated with fat percentage at 4 years. Conclusion Several cord blood kynurenine metabolite concentrations were positively associated with birthweight, with higher kynurenic acid and quinolinic acid correlating to higher percentage body fat in childhood, suggesting these cord blood metabolites as biomarkers of early childhood adiposity.