Browsing by Subject " metabolism"

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  • Mannisto, Ville T.; Simonen, Marko; Soininen, Pasi; Tiainen, Mika; Kangas, Antti J.; Kaminska, Dorota; Venesmaa, Sari; Kakela, Pirjo; Karja, Vesa; Gylling, Helena; Ala-Korpela, Mika; Pihlajamaki, Jussi (2014)
  • Muha, Villo; Williamson, Ritchie; Hills, Rachel; McNeilly, A.D.; McWilliams, T.G.; Alonso, Jana; Schimpl, Marianne; Leney, Aneika C.; Heck, Albert J.R.; Sutherland, Calum; Read, Kevin D.; McCrimmon, Rory J.; Brooks, S.P.; Van Aalten, Daan M.F. (2019)
    O-GlcNAcylation is an abundant post-translational modification in the nervous system, linked to both neurodevelopmental and neurodegenerative disease. However, the mechanistic links between these phenotypes and site-specific O-GlcNAcylation remain largely unexplored. Here, we show that Ser517 O-GlcNAcylation of the microtubule-binding protein Collapsin Response Mediator Protein-2 (CRMP2) increases with age. By generating and characterizing a Crmp2S517A knock-in mouse model, we demonstrate that loss of O-GlcNAcylation leads to a small decrease in body weight and mild memory impairment, suggesting that Ser517 O-GlcNAcylation has a small but detectable impact on mouse physiology and cognitive function. © 2019 The Authors. Published by the Royal Society under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/4.0/, which permits unrestricted use, provided the original author and source are credited.
  • Wasenius, Niko S.; Isomaa, Bo A.; Östman, Bjarne; Söderström, Johan; Forsen, Björn; Lahti, Kaj; Hakaste, Liisa; Eriksson, Johan G.; Groop, Leif; Hansson, Ola; Tuomi, Tiinamaija (2020)
    Introduction To investigate the effect of an exercise prescription and a 1-year supervised exercise intervention, and the modifying effect of the family history of type 2 diabetes (FH), on long-term cardiometabolic health. Research design and methods For this prospective randomized trial, we recruited non-diabetic participants with poor fitness (n=1072, 30-70 years). Participants were randomly assigned with stratification for FH either in the exercise prescription group (PG, n=144) or the supervised exercise group (EG, n=146) group and compared with a matched control group from the same population study (CON, n=782). The PG and EG received exercise prescriptions. In addition, the EG attended supervised exercise sessions two times a week for 60 min for 12 months. Cardiometabolic risk factors were measured at baseline, 1 year, 5 years, and 6 years. The CON group received no intervention and was measured at baseline and 6 years. Results The EG reduced their body weight, waist circumference, diastolic blood pressure, and low-density lipoprotein-cholesterol (LDL-C) but not physical fitness (p=0.074) or insulin or glucose regulation (p>0.1) compared with the PG at 1 year and 5 years (p Conclusions Low-cost physical activity programs have long-term beneficial effects on cardiometabolic health regardless of the FH of diabetes. Given the feasibility and low cost of these programs, they should be advocated to promote cardiometabolic health.
  • Rolova, Taisia; Lehtonen, Sarka; Goldsteins, Gundars; Kettunen, Pinja; Koistinaho, Jari (2021)
    The research on neurodegenerative disorders has long focused on neuronal pathology and used transgenic mice as disease models. However, our understanding of the chronic neurodegenerative process in the human brain is still very limited. It is increasingly recognized that neuronal loss is not caused solely by intrinsic degenerative processes but rather via impaired interactions with surrounding glia and other brain cells. Dysfunctional astrocytes do not provide sufficient nutrients and antioxidants to the neurons, while dysfunctional microglia cannot efficiently clear pathogens and cell debris from extracellular space, thus resulting in chronic inflammatory processes in the brain. Importantly, human glia, especially the astrocytes, differ significantly in morphology and function from their mouse counterparts, and therefore more human-based disease models are needed. Recent advances in stem cell technology make it possible to reprogram human patients' somatic cells to induced pluripotent stem cells (iPSC) and differentiate them further into patient-specific glia and neurons, thus providing a virtually unlimited source of human brain cells. This review summarizes the recent studies using iPSC-derived glial models of Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis and discusses the applicability of these models to drug testing. This line of research has shown that targeting glial metabolism can improve the survival and function of cocultured neurons and thus provide a basis for future neuroprotective treatments.
  • Hovinen, Topi (Helsingfors universitet, 2016)
    Folate deficiency (FD) has been found to cause number of medical conditions varying from megaloblastic anemia to fetal neural tube defects but the molecular basis behind these has remained poorly understood. We studied the metabolic consequences of FD in mouse liver and brain, concentrating on transsulfuration pathway and cysteine-dependent pathways. Data was acquired with mass spectrometry based metabolomics and western blotting. We found that FD induces lack of cysteine in liver and brain, causing further imbalances in cysteine-derived metabolites such as glutathione and taurine. Changes in enzyme expression show that hepatic cells prioritize glutathione synthesis over taurine synthesis, while the brain does vice versa. We then supplemented FD mice with N-acetylcysteine (NAC), precursor of cysteine. NAC supplementation restored hepatic bile acid and blood glutathione levels of FD tissues. These results improved our understanding of FD induced metabolic imbalances and proved that NAC significantly rescues some of these changes.
  • Parviainen, Heli (Helsingin yliopisto, 2020)
    Statins are a commonly used group of drugs that reduce the cholesterol levels in blood and have been shown to reduce cardiovascular morbidity and mortality. However, a considerable percentage of patients experience adverse effects during statin treatment. Statin adverse effects have been associated with genetic polymorphisms and drug-drug interactions that affect the elimination and active transport of these drugs. A more comprehensive knowledge of statin metabolism may be a step towards better management of statin treatments. Statin metabolism both in vivo and in vitro has been subject of study for years. In vitro incubation conditions may considerably affect the observed clearance, and results obtained with different methods or in different laboratories may not be directly comparable to each other. No single in vitro study on a wide panel of statins has previously been conducted. Six statins and some of their metabolites, fourteen compounds in total, were included in the study. The intrinsic clearance (CLint) of these molecules was investigated in vitro on human liver microsomes (HLM) and a panel of eleven cytochrome P450 (CYP) enzymes recombinantly expressed in E. coli. Observed CLint values for each compound in HLM and for each compound-CYP pair with observed depletion were calculated. The percentual contributions of each CYP enzyme to the metabolism of the compounds was calculated. The results obtained with recombinant CYP enzymes (rcCYP) were complemented with studies on HLM with specific chemical inhibitors of CYP enzymes. In this study the metabolism of statin lactones seemed to be faster than the metabolism of the corresponding statin acids. Atorvastatin lactone, 2-hydroxy atorvastatin lactone, 4-hydroxy atorvastatin lactone and simvastatin were extensively metabolized. Atorvastatin, 2-hydroxy atorvastatin, 3R,5S-fluvastatin, 3S,5R-fluvastatin, pitavastatin lactone and simvastatin acid showed intermediate metabolism. 4-hydroxy atorvastatin, pitavastatin, pravastatin and rosuvastatin rates of metabolism were below quantification limit. CYP3A4 had a major role in the metabolism of atorvastatin and its metabolites, simvastatin and simvastatin acid. CYP3A4 also had activity towards pitavastatin lactone. CYP2C9 had a high activity towards both 3R,5S-fluvastatin and 3S,5R-fluvastatin. CYP2D6 may play a part in the metabolism of pitavastatin lactone. CYP2C8 may have some activity towards simvastatin and simvastatin acid. The data is mostly in agreement with previous in vitro and in vivo studies regarding both the metabolism rate of statins and the contributions by different CYP enzymes to the metabolism of statins. Due to the screening nature of the study and some methodological constraints, these data should be considered as preliminary and require confirmation in further studies.
  • Tervahauta, Tuomas (Helsingfors universitet, 2015)
    Prodrugs are pharmacologically inactive molecules which undergo metabolic bioactivation in vivo to form pharmaceutically active agents. Prodrugs have been designed to improve so called drug-like properties of active parent compounds (APC) i.e. to increase solubility or absorption and to reduce first-pass metabolism etc. In this master's thesis the goal was to establish non-cell-based in vitro methods to study prodrug bioactivation. Four commercially available prodrugs (bambuterol, olmesartan medoxomil (OM), candesartan cilexetil (CC) and famciclovir) were used as test compounds. The prodrugs were incubated in liver and intestinal S9 fractions and blood plasma to study in vitro bioactivation of these prodrugs. Other metabolism of the prodrug and APC (nonproductive metabolism) was studied by comparing incubation with and without cofactors of metabolizing enzymes. Species differences was studied using human, rat and dog matrices. Prodrug concentrations were quantified from the incubation samples using liquid chromatography- tandem mass spectrometry (LC-MSMS) methods developed for this study. Additionally the effect of promoiety on passive permeability was studied with parallel artificial membrane permeability assay (PAMPA). All of the studied prodrugs produced at least low concentrations of APC in one or more incubations. Terbutaline (APC of bambuterol) formation was observed in human plasma and was concentration dependent which is consisted with the literature. Olmesartan and candesartan were formed in S9 fraction in high rate, but not in buffer: indicating enzyme mediated hydrolysis. However, based on literature CC hydrolysis was not expected to occur in intestinal S9 fractions. Penciclovir (APC of famciclovir) was formed only in presence of human or rat liver S9 fraction which was in line with the pre-existing literature. With the method used the nonproductive metabolism could not be estimated. In PAMPA bambuterol, famciclovir and OM had higher permeability than corresponding APCs whereas CC was only more permeable than candesartan in pH 7.4. The in vitro incubation used in this study can be used for screening prodrugs. However both low and high activation rates were observed thus the clinically relevant in vivo APC formation can be achieved with both high and low bioactivation in vitro. Studying the rate of prodrug formation alone estimations about clinically relevant bioactivation rates cannot be concluded. No clear signs of nonproductive could be seen with the prodrugs studied with current method. For the estimation of nonproductive metabolism, metabolite screening studies would need to be developed and conducted parallel to studies prescribed in this master's thesis.
  • Pinola, Pekka; Puukka, Katri; Piltonen, Terhi T.; Puurunen, Johanna; Vanky, Eszter; Sundström-Poromaa, Inger; Stener-Victorin, Elisabet; Hirschberg, Angelica Linden; Ravn, Pernille; Andersen, Marianne Skovsager; Glintborg, Dorte; Mellembakken, Jan Roar; Ruokonen, Aimo; Tapanainen, Juha; Morin-Papunen, Laure C. (2017)
    Objective: To compare the metabolic profiles of normo- and hyperandrogenic women with polycystic ovary syndrome (PCOS) with those of control women at different ages during reproductive life. Design: Case-control study. Setting: Not applicable. Patient(s): In all, 1,550 women with normoandrogenic (n = 686) or hyperandrogenic (n = 842) PCOS and 447 control women were divided into three age groups: <30, 30-39, and > 39 years). Interventions(s): None. Main Outcome Measure(s): Body mass index (BMI), waist circumference, blood pressure, glucose, insulin, cholesterol, lipoproteins, triglycerides and high-sensitivity C-reactive protein. Result(s): Both normo- and hyperandrogenic women with PCOS were more obese, especially abdominally. They had increased serum levels of insulin (fasting and in oral glucose tolerance tests), triglycerides, low-density lipoprotein, and total cholesterol, higher blood pressure, and lower high-density lipoprotein levels independently from BMI compared with the control population as early as from young adulthood until menopause. The prevalence of metabolic syndrome was two-to fivefold higher in women with PCOS compared with control women, depending on age and phenotype, and the highest prevalence was observed in hyperandrogenic women with PCOS at late reproductive age. Conclusion(s): When evaluating metabolic risks in women with PCOS, androgenic status, especially abdominal obesity and age, should be taken into account, which would allow tailored management of the syndrome from early adulthood on. (C) 2016 by American Society for Reproductive Medicine.
  • Tonttila, Kialiina (Helsingin yliopisto, 2021)
    Respirometry is a polarographic method that provides insights into mitochondrial respiratory capacity – specifically to electron transport chain (ETC) complexes I to V –, mitochondrial integrity and energy metabolism. The limitation of the respiratory measurements has been that it requires freshly isolated mitochondria or tissue sample. Long-term preservation of mitochondrial function in frozen samples has been a considerable challenge, since the membrane integrity of the mitochondria is lost during the freezing process. Thus, samples do not display coupled respiration. However, previous studies have found that despite coupled respiration is impaired the individual ETC complexes and the ability of ETC supercomplexes to consume oxygen are not destroyed due to freezing and thawing. On the basis of this knowledge, recently published article presented a novel protocol that overcomes the damages caused by freeze-thaw cycles. The protocol also enables respiration measurement of ETC complexes I-IV by using Seahorse XF96 Extracellular flux analyzer. In this MSc thesis I modified and optimized the aforementioned protocol for Oroboros O2k high- resolution respirometry using frozen skeletal muscle samples. In addition, this study provides an optimized sample preparation protocol for frozen muscle samples and respiration measurement. The new method broadens the possibilities within mitochondrial respiration studies since Oroboros O2k high-resolution respirometry records results with high sensitivity without limiting the number of substrates used. The possibility to use frozen samples reduces research costs, simplifies logistics and enables retrospective studies with previously stored frozen tissue samples. I also utilized the optimized respiration measurement protocol to study metabolic effects of combined gene therapy in skeletal muscle. This gene therapy mimics the positive effects of exercise by inducing skeletal muscle growth and angiogenesis. The mimicking effect was induced by systemic delivery of adeno-associated viral vectors encoding pro-myostatin and VEGF-B. In previous studies inhibition of myostatin has been connected to compromised oxidative capacity and vascular rarefaction. In contrast, VEGF-B has demonstrated to induce angiogenesis in several tissues. Thus, my hypothesis was that combination gene therapy would result in better mitochondrial function than pro-myostatin alone. Results from this study indicate that moderate inhibition of myostatin signaling by pro-myostatin using rAAV vectors could provide enhancements in ETC function when it is induced independently or combined with rAAV-VEGF-B. This result lays a solid foundation for future research and could provide a new therapeutic option against muscle loss and related metabolic diseases.
  • Siltari, Aino; Auvinen, Anssi; Murtola, Teemu J. (2021)
    Simple Summary Pharmacoepidemiologic research provides opportunities to evaluate how commonly used drug groups, such as cholesterol-lowering drugs, may affect the prostate cancer risk or mortality. However, such studies need to be carefully designed in order to avoid biases caused by systematic differences between medication users and non-users. Similarly, data must be carefully analyzed and interpreted while acknowledging possible biases that can lead to erroneous conclusions. Here, we review common pitfalls in such studies and describe ways to avoid them in an effort to aid future research. Pharmacoepidemiologic research provides opportunities to evaluate how commonly used drug groups, such as cholesterol-lowering or antidiabetic drugs, may affect the prostate cancer risk or mortality. This type of research is valuable in estimating real-life drug effects. Nonetheless, pharmacoepidemiological studies are prone to multiple sources of bias that mainly arise from systematic differences between medication users and non-users. If these are not appreciated and properly controlled for, there is a risk of obtaining biased results and reaching erroneous conclusions. Therefore, in order to improve the quality of future research, we describe common biases in pharmacoepidemiological studies, particularly in the context of prostate cancer research. We also list common ways to mitigate these biases and to estimate causality between medication use and cancer outcomes.
  • Lensu, Sanna; Pariyani, Raghunath; Mäkinen, Elina; Yang, Baoru; Saleem, Wisam; Munukka, Eveliina; Lehti, Maarit; Driuchina, Anastasiia; Linden, Jere; Tiirola, Marja; Lahti, Leo; Pekkala, Satu (2020)
    Understanding the importance of the gut microbiota (GM) in non-alcoholic fatty liver disease (NAFLD) has raised the hope for therapeutic microbes. We have shown that high hepatic fat content associated with low abundance of Faecalibacterium prausnitzii in humans and, further, the administration of F. prausnitzii prevented NAFLD in mice. Here, we aimed at targeting F. prausnitzii by prebiotic xylo-oligosaccharides (XOS) to treat NAFLD. First, the effect of XOS on F. prausnitzii growth was assessed in vitro. Then, XOS was supplemented or not with high (HFD, 60% of energy from fat) or low (LFD) fat diet for 12 weeks in Wistar rats (n = 10/group). XOS increased F. prausnitzii growth, having only a minor impact on the GM composition. When supplemented with HFD, XOS ameliorated hepatic steatosis. The underlying mechanisms involved enhanced hepatic beta-oxidation and mitochondrial respiration. Nuclear magnetic resonance (H-1-NMR) analysis of cecal metabolites showed that, compared to the HFD, the LFD group had a healthier cecal short-chain fatty acid profile and on the HFD, XOS reduced cecal isovalerate and tyrosine, metabolites previously linked to NAFLD. Cecal branched-chain fatty acids associated positively and butyrate negatively with hepatic triglycerides. In conclusion, XOS supplementation can ameliorate NAFLD by improving hepatic oxidative metabolism and affecting GM.
  • Saukkonen, K.; Hagström, J.; Mustonen, H.; Lehtinen, Laura; Carpen, O.; Andersson, L.C.; Seppänen, H.; Haglund, C. (2018)
    Expression of regenerating islet-derived protein 4 (REG4), a secretory protein involved in cell differentiation and proliferation, is upregulated in inflammatory bowel diseases and in many gastrointestinal malignancies. The prognostic significance of its expression in pancreatic ductal adenocarcinoma is unknown. Our aim was to investigate tumor tissue and serum REG4 expression in pancreatic ductal adenocarcinoma patients. We also evaluated as a control the diagnostic value of serum REG4 level in patients with chronic pancreatitis. Immunohistochemical expression of REG4 was evaluated in 154 surgical specimens and serum REG4 level in 130 samples from pancreatic ductal adenocarcinoma patients treated at Helsinki University Hospital, Finland, in 2000–2011. REG4 tissue and serum expression was assessed in relation to clinicopathological parameters and patient survival. A chronic pancreatitis control group comprised 34 patients who underwent pancreatic resection because of suspicion of malignancy. Significant survival differences were detectable in subgroups: in tumor stages IA–IIA, high serum REG4 level predicted worse survival (p=0.046). In patients with grade I tumor, positive tissue REG4 expression predicted better survival (p=0.006). In multivariate analysis, neither tissue nor serum REG4 expression was independent prognostic factors. Serum REG4 levels were higher in pancreatic ductal adenocarcinoma than in chronic pancreatitis (p=0.002), with diagnostic sensitivity of 45% and specificity of 91%. In logistic regression analysis, a multivariate model with REG4, CA19-9, and age provided sensitivity of 82% and specificity of 79%. REG4 tissue expression is a prognostic marker in subgroups of pancreatic ductal adenocarcinoma patients. Serum REG4 level might be useful in differential diagnosis between pancreatic ductal adenocarcinoma and chronic pancreatitis. © 2018, © The Author(s) 2018.
  • Durian, Guido; Rahikainen, Moona; Alegre, Sara; Brosche, Mikael; Kangasjarvi, Saijaliisa (2016)
    Biotic stress factors pose a major threat to plant health and can significantly deteriorate plant productivity by impairing the physiological functions of the plant. To combat the wide range of pathogens and insect herbivores, plants deploy converging signaling pathways, where counteracting activities of protein kinases and phosphatases form a basic mechanism for determining appropriate defensive measures. Recent studies have identified Protein Phosphatase 2A (PP2A) as a crucial component that controls pathogenesis responses in various plant species. Genetic, proteomic and metabolomic approaches have underscored the versatile nature of PP2A, which contributes to the regulation of receptor signaling, organellar signaling, gene expression, metabolic pathways, and cell death, all of which essentially impact plant immunity. Associated with this, various PP2A subunits mediate post-translational regulation of metabolic enzymes and signaling components. Here we provide an overview of protein kinase/phosphatase functions in plant immunity signaling, and position the multifaceted functions of PP2A in the tightly inter-connected regulatory network that controls the perception, signaling and responding to biotic stress agents in plants.
  • Konttinen, Henna; Cabral-da-Silva, Mauricio e Castro; Ohtonen, Sohvi; Wojciechowski, Sara; Shakirzyanova, Anastasia; Caligola, Simone; Giugno, Rosalba; Ishchenko, Yevheniia; Hernández, Damián; Fazaludeen, Mohammad Feroze; Eamen, Shaila; Budia, Mireia Gómez; Fagerlund, Ilkka; Scoyni, Flavia; Korhonen, Paula; Huber, Nadine; Haapasalo, Annakaisa; Hewitt, Alex W.; Vickers, James; Smith, Grady C.; Oksanen, Minna; Graff, Caroline; Kanninen, Katja M.; Lehtonen, Sarka; Propson, Nicholas; Schwartz, Michael P.; Pébay, Alice; Koistinaho, Jari; Ooi, Lezanne; Malm, Tarja (2019)
    Summary Here we elucidate the effect of Alzheimer disease (AD)-predisposing genetic backgrounds, APOE4, PSEN1ΔE9, and APPswe, on functionality of human microglia-like cells (iMGLs). We present a physiologically relevant high-yield protocol for producing iMGLs from induced pluripotent stem cells. Differentiation is directed with small molecules through primitive erythromyeloid progenitors to re-create microglial ontogeny from yolk sac. The iMGLs express microglial signature genes and respond to ADP with intracellular Ca2+ release distinguishing them from macrophages. Using 16 iPSC lines from healthy donors, AD patients and isogenic controls, we reveal that the APOE4 genotype has a profound impact on several aspects of microglial functionality, whereas PSEN1ΔE9 and APPswe mutations trigger minor alterations. The APOE4 genotype impairs phagocytosis, migration, and metabolic activity of iMGLs but exacerbates their cytokine secretion. This indicates that APOE4 iMGLs are fundamentally unable to mount normal microglial functionality in AD.
  • El-Khaledl, Yusuf C.; Roth, Florian; Rädecker, Nils; Kharbatia, Najeh; Jones, Burton H.; Voolstra, Christian R.; Wild, Christian (2020)
    Nitrogen (N) cycling in coral reefs is of key importance for these oligotrophic ecosystems, but knowledge about its pathways is limited. While dinitrogen (N-2) fixation is comparably well studied, the counteracting denitrification pathway is under-investigated, mainly because of expensive and relatively complex experimental techniques currently available. Here, we combined two established acetylene-based assays to one single setup to determine N-2-fixation and denitrification performed by microbes associated with coral reef substrates/organisms simultaneously. Accumulating target gases (ethylene for N-2-fixation, nitrous oxide for denitrification) were measured in gaseous headspace samples via gas chromatography. We measured N-2-fixation and denitrification rates of two Red Sea coral reef substrates (filamentous turf algae, coral rubble), and demonstrated, for the first time, the co-occurrence of both N-cycling processes in both substrates. N-2-fixation rates were up to eight times higher during the light compared to the dark, whereas denitrification rates during dark incubations were stimulated for turf algae and suppressed for coral rubble compared to light incubations. Our results highlight the importance of both substrates in fixing N, but their role in relieving N is potentially divergent. Absolute N-2-fixation rates of the present study correspond with rates reported previously, even though likely underestimated due to an initial lag phase. Denitrification is also presumably underestimated due to incomplete nitrous oxide inhibition and/or substrate limitation. Besides these inherent limitations, we show that a relative comparison of N-2-fixation and denitrification activity between functional groups is possible. Thus, our approach facilitates cost-efficient sample processing in studies interested in comparing relative rates of N-2-fixation and denitrification.
  • Al-Rashed, F.; Ahmad, Z.; Iskandar, M.A.; Tuomilehto, J.; Al-Mulla, F.; Ahmad, R. (2019)
    Background/Aims: TNF-α-mediated pro-inflammatory phenotypic change in monocytes is known to be implicated in the pathogenesis of metabolic inflammation and insulin resistance. However, the mechanism by which TNF-α-induces inflammatory phenotypic shift in monocytes is poorly understood. Since long-chain acyl-CoA synthetase 1 (ACSL1) is associated with inflammatory monocytes/macrophages, we investigated the role of ACSL1 in the TNF-α-driven inflammatory phenotypic shift in the monocytes. Methods: Monocytes (Human monocytic THP-1 cells) were stimulated with TNF-α. Inflammatory phenotypic markers (CD16, CD11b, CD11c and HLA-DR) expression was determined with real time RT-PCR and flow cytometry. IL-1β and MCP-1 were determined by ELISA. Signaling pathways were identified by using ACSL1 inhibitor, ACSL1 siRNA and NF-κB reporter monocytic cells. Phosphorylation of NF-κB was analyzed by western blotting and flow cytometry. Results: Our data show that TNF-α induced significant increase in the expression of CD16, CD11b, CD11c and HLA-DR. Inhibition of ACSL1 activity in the cells with triacsin C significantly suppressed the expression of these inflammatory markers. Using ACSL-1 siRNA, we further demonstrate that TNF-α-induced inflammatory markers expression in monocytic cells requires ACSL1. In addition, IL-1b and MCP-1 production by TNF-α activated monocytic cells was significantly blocked by the inhibition of ACSL-1 activity. Interestingly, elevated NF-κB activity resulting from TNF-α stimulation was attenuated in ACSL1 deficient cells. Conclusion: Our findings provide an evidence that TNF-α-associated inflammatory polarization in monocytes is an ACSL1 dependent process, which indicates its central role in TNF-α-driven metabolic inflammation. © 2019 The Author(s).
  • Ollila, Hanna Maria; Utge, S; Kronholm, E; van Leeuwen, W; Silander, Kaisa; Partonen, T; Perola, Markus; Kaprio, Jaakko; Salomaa, V; Sallinen, M; Härmä, M; Porkka-Heiskanen, Tarja; Paunio, Tiina (2012)
    Epidemiological studies show association between sleep duration and lipid metabolism. In addition, inactivation of circadian genes induces insulin resistance and hyperlipidemia. We hypothesized that sleep length and lipid metabolism are partially controlled by the same genes. We studied the association of total sleep time (TST) with 60 genetic variants that had previously been associated with lipids. The analyses were performed in a Finnish population-based sample (N = 6334) and replicated in 2189 twins. Finally, RNA expression from mononuclear leucocytes was measured in 10 healthy volunteers before and after sleep restriction. The genetic analysis identified two variants near TRIB1 gene that independently contributed to both blood lipid levels and to TST (rs17321515, P = 8.92(*)10(-5), Bonferroni corrected P = 0.0053, β = 0.081 h per allele; rs2954029, P = 0.00025, corrected P = 0.015, β = 0.076; P<0.001 for both variants after adjusting for blood lipid levels or body mass index). The finding was replicated in the twin sample (rs17321515, P = 0.022, β = 0.063; meta-analysis of both samples P = 8.1(*)10(-6), β = 0.073). After the experimentally induced sleep restriction period TRIB1 expression increased 1.6-fold and decreased in recovery phase (P = 0.006). In addition, a negative correlation between TRIB1 expression and slow wave sleep was observed in recovery from sleep restriction. These results show that allelic variants of TRIB1 are independently involved in regulation of lipid metabolism and sleep. The findings give evidence for the pleiotropic nature of TRIB1 and may reflect the shared roots of sleep and metabolism. The shared genetic background may at least partially explain the mechanism behind the well-established connection between diseases with disrupted metabolism and sleep.
  • Waldenström macroglobulinemia Group (2018)
    Waldenström macroglobulinemia (WM)/lymphoplasmacytic lymphoma (LPL) is a rare, chronic B-cell lymphoma with high heritability. We conduct a two-stage genome-wide association study of WM/LPL in 530 unrelated cases and 4362 controls of European ancestry and identify two high-risk loci associated with WM/LPL at 6p25.3 (rs116446171, near EXOC2 and IRF4; OR = 21.14, 95% CI: 14.40–31.03, P = 1.36 × 10 −54 ) and 14q32.13 (rs117410836, near TCL1; OR = 4.90, 95% CI: 3.45–6.96, P = 8.75 × 10 −19 ). Both risk alleles are observed at a low frequency among controls (~2–3%) and occur in excess in affected cases within families. In silico data suggest that rs116446171 may have functional importance, and in functional studies, we demonstrate increased reporter transcription and proliferation in cells transduced with the 6p25.3 risk allele. Although further studies are needed to fully elucidate underlying biological mechanisms, together these loci explain 4% of the familial risk and provide insights into genetic susceptibility to this malignancy. © 2018, The Author(s).
  • Hovinen, Topi; Korkalo, Liisa; Freese, Riitta; Skaffari, Essi; Isohanni, Pirjo; Niemi, Mikko; Nevalainen, Jaakko; Gylling, Helena; Zamboni, Nicola; Erkkola, Maijaliisa; Suomalainen, Anu (2021)
    Vegan diets are gaining popularity, also in families with young children. However, the effects of strict plant-based diets on metabolism and micronutrient status of children are unknown. We recruited 40 Finnish children with a median age 3.5 years-vegans, vegetarians, or omnivores from same daycare centers-for a cross-sectional study. They enjoyed nutritionist-planned vegan or omnivore meals in daycare, and the full diets were analyzed with questionnaires and food records. Detailed analysis of serum metabolomics and biomarkers indicated vitamin A insufficiency and border-line sufficient vitamin D in all vegan participants. Their serum total, HDL and LDL cholesterol, essential amino acid, and docosahexaenoic n-3 fatty acid (DHA) levels were markedly low and primary bile acid biosynthesis, and phospholipid balance was distinct from omnivores. Possible combination of low vitamin A and DHA status raise concern for their visual health. Our evidence indicates that (i) vitamin A and D status of vegan children requires special attention; (ii) dietary recommendations for children cannot be extrapolated from adult vegan studies; and (iii) longitudinal studies on infant-onset vegan diets are warranted.
  • Kivelä, Milla Riikka; Bry, Maija; Robciuc, Marius R.; Räsänen, Markus; Taavitsainen, Miia; Silvola, Johanna M. U.; Saraste, Antti; Hulmi, Juha J.; Anisimov, Andrey; Mayranpaa, Mikko I.; Lindeman, Jan H.; Eklund, Lauri; Hellberg, Sanna; Hlushchuk, Ruslan; Zhuang, Zhen W.; Simons, Michael; Djonov, Valentin; Knuuti, Juhani; Mervaala, Eero; Alitalo, Kari (2014)