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  1. AU="Laxman Yetukuri"
  2. AU="Bazan, Dominika"

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  1. Article ; Online: Development of actionable targets of multi-kinase inhibitors (AToMI) screening platform to dissect kinase targets of staurosporines in glioblastoma cells

    Oxana V. Denisova / Joni Merisaari / Amanpreet Kaur / Laxman Yetukuri / Mikael Jumppanen / Carina von Schantz-Fant / Michael Ohlmeyer / Krister Wennerberg / Tero Aittokallio / Mikko Taipale / Jukka Westermarck

    Scientific Reports, Vol 12, Iss 1, Pp 1-

    2022  Volume 9

    Abstract: Abstract Therapeutic resistance to kinase inhibitors constitutes a major unresolved clinical challenge in cancer and especially in glioblastoma. Multi-kinase inhibitors may be used for simultaneous targeting of multiple target kinases and thereby ... ...

    Abstract Abstract Therapeutic resistance to kinase inhibitors constitutes a major unresolved clinical challenge in cancer and especially in glioblastoma. Multi-kinase inhibitors may be used for simultaneous targeting of multiple target kinases and thereby potentially overcome kinase inhibitor resistance. However, in most cases the identification of the target kinases mediating therapeutic effects of multi-kinase inhibitors has been challenging. To tackle this important problem, we developed an actionable targets of multi-kinase inhibitors (AToMI) strategy and used it for characterization of glioblastoma target kinases of staurosporine derivatives displaying synergy with protein phosphatase 2A (PP2A) reactivation. AToMI consists of interchangeable modules combining drug-kinase interaction assay, siRNA high-throughput screening, bioinformatics analysis, and validation screening with more selective target kinase inhibitors. As a result, AToMI analysis revealed AKT and mitochondrial pyruvate dehydrogenase kinase PDK1 and PDK4 as kinase targets of staurosporine derivatives UCN-01, CEP-701, and K252a that synergized with PP2A activation across heterogeneous glioblastoma cells. Based on these proof-of-principle results, we propose that the application and further development of AToMI for clinically applicable multi-kinase inhibitors could provide significant benefits in overcoming the challenge of lack of knowledge of the target specificity of multi-kinase inhibitors.
    Keywords Medicine ; R ; Science ; Q
    Language English
    Publishing date 2022-08-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Multi-Omics Studies towards Novel Modulators of Influenza A Virus–Host Interaction

    Sandra Söderholm / Yu Fu / Lana Gaelings / Sergey Belanov / Laxman Yetukuri / Mikhail Berlinkov / Anton V. Cheltsov / Simon Anders / Tero Aittokallio / Tuula A. Nyman / Sampsa Matikainen / Denis E. Kainov

    Viruses, Vol 8, Iss 10, p

    2016  Volume 269

    Abstract: Human influenza A viruses (IAVs) cause global pandemics and epidemics. These viruses evolve rapidly, making current treatment options ineffective. To identify novel modulators of IAV–host interactions, we re-analyzed our recent transcriptomics, ... ...

    Abstract Human influenza A viruses (IAVs) cause global pandemics and epidemics. These viruses evolve rapidly, making current treatment options ineffective. To identify novel modulators of IAV–host interactions, we re-analyzed our recent transcriptomics, metabolomics, proteomics, phosphoproteomics, and genomics/virtual ligand screening data. We identified 713 potential modulators targeting 199 cellular and two viral proteins. Anti-influenza activity for 48 of them has been reported previously, whereas the antiviral efficacy of the 665 remains unknown. Studying anti-influenza efficacy and immuno/neuro-modulating properties of these compounds and their combinations as well as potential viral and host resistance to them may lead to the discovery of novel modulators of IAV–host interactions, which might be more effective than the currently available anti-influenza therapeutics.
    Keywords influenza virus ; antiviral agent ; proteomics ; phosphoproteomics ; metabolomics ; transcriptomics ; genomics ; virtual ligand screening ; Microbiology ; QR1-502 ; Science ; Q
    Language English
    Publishing date 2016-09-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: High density lipoprotein structural changes and drug response in lipidomic profiles following the long-term fenofibrate therapy in the FIELD substudy.

    Laxman Yetukuri / Ilkka Huopaniemi / Artturi Koivuniemi / Marianna Maranghi / Anne Hiukka / Heli Nygren / Samuel Kaski / Marja-Riitta Taskinen / Ilpo Vattulainen / Matti Jauhiainen / Matej Orešič

    PLoS ONE, Vol 6, Iss 8, p e

    2011  Volume 23589

    Abstract: In a recent FIELD study the fenofibrate therapy surprisingly failed to achieve significant benefit over placebo in the primary endpoint of coronary heart disease events. Increased levels of atherogenic homocysteine were observed in some patients assigned ...

    Abstract In a recent FIELD study the fenofibrate therapy surprisingly failed to achieve significant benefit over placebo in the primary endpoint of coronary heart disease events. Increased levels of atherogenic homocysteine were observed in some patients assigned to fenofibrate therapy but the molecular mechanisms behind this are poorly understood. Herein we investigated HDL lipidomic profiles associated with fenofibrate treatment and the drug-induced Hcy levels in the FIELD substudy. We found that fenofibrate leads to complex HDL compositional changes including increased apoA-II, diminishment of lysophosphatidylcholines and increase of sphingomyelins. Ethanolamine plasmalogens were diminished only in a subgroup of fenofibrate-treated patients with elevated homocysteine levels. Finally we performed molecular dynamics simulations to qualitatively reconstitute HDL particles in silico. We found that increased number of apoA-II excludes neutral lipids from HDL surface and apoA-II is more deeply buried in the lipid matrix than apoA-I. In conclusion, a detailed molecular characterization of HDL may provide surrogates for predictors of drug response and thus help identify the patients who might benefit from fenofibrate treatment.
    Keywords Medicine ; R ; Science ; Q
    Subject code 610
    Language English
    Publishing date 2011-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: Triacylglycerol fatty acid composition in diet-induced weight loss in subjects with abnormal glucose metabolism--the GENOBIN study.

    Ursula Schwab / Tuulikki Seppänen-Laakso / Laxman Yetukuri / Jyrki Agren / Marjukka Kolehmainen / David E Laaksonen / Anna-Liisa Ruskeepää / Helena Gylling / Matti Uusitupa / Matej Oresic / GENOBIN Study Group

    PLoS ONE, Vol 3, Iss 7, p e

    2008  Volume 2630

    Abstract: The effect of weight loss on different plasma lipid subclasses at the molecular level is unknown. The aim of this study was to examine whether a diet-induced weight reduction result in changes in the extended plasma lipid profiles (lipidome) in subjects ... ...

    Abstract The effect of weight loss on different plasma lipid subclasses at the molecular level is unknown. The aim of this study was to examine whether a diet-induced weight reduction result in changes in the extended plasma lipid profiles (lipidome) in subjects with features of metabolic syndrome in a 33-week intervention.Plasma samples of 9 subjects in the weight reduction group and 10 subjects in the control group were analyzed using mass spectrometry based lipidomic and fatty acid analyses. Body weight decreased in the weight reduction group by 7.8+/-2.9% (p<0.01). Most of the serum triacylglycerols and phosphatidylcholines were reduced. The decrease in triacylglycerols affected predominantly the saturated short chain fatty acids. This decrease of saturated short chain fatty acid containing triacylglycerols correlated with the increase of insulin sensitivity. However, levels of several longer chain fatty acids, including arachidonic and docosahexanoic acid, were not affected by weight loss. Levels of other lipids known to be associated with obesity such as sphingolipids and lysophosphatidylcholines were not altered by weight reduction.Diet-induced weight loss caused significant changes in global lipid profiles in subjects with abnormal glucose metabolism. The observed changes may affect insulin sensitivity and glucose metabolism in these subjects.ClinicalTrials.gov NCT00621205.
    Keywords Medicine ; R ; Science ; Q
    Subject code 796
    Language English
    Publishing date 2008-07-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: Metabolic regulation in progression to autoimmune diabetes.

    Marko Sysi-Aho / Andrey Ermolov / Peddinti V Gopalacharyulu / Abhishek Tripathi / Tuulikki Seppänen-Laakso / Johanna Maukonen / Ismo Mattila / Suvi T Ruohonen / Laura Vähätalo / Laxman Yetukuri / Taina Härkönen / Erno Lindfors / Janne Nikkilä / Jorma Ilonen / Olli Simell / Maria Saarela / Mikael Knip / Samuel Kaski / Eriika Savontaus /
    Matej Orešič

    PLoS Computational Biology, Vol 7, Iss 10, p e

    2011  Volume 1002257

    Abstract: Recent evidence from serum metabolomics indicates that specific metabolic disturbances precede β-cell autoimmunity in humans and can be used to identify those children who subsequently progress to type 1 diabetes. The mechanisms behind these disturbances ...

    Abstract Recent evidence from serum metabolomics indicates that specific metabolic disturbances precede β-cell autoimmunity in humans and can be used to identify those children who subsequently progress to type 1 diabetes. The mechanisms behind these disturbances are unknown. Here we show the specificity of the pre-autoimmune metabolic changes, as indicated by their conservation in a murine model of type 1 diabetes. We performed a study in non-obese prediabetic (NOD) mice which recapitulated the design of the human study and derived the metabolic states from longitudinal lipidomics data. We show that female NOD mice who later progress to autoimmune diabetes exhibit the same lipidomic pattern as prediabetic children. These metabolic changes are accompanied by enhanced glucose-stimulated insulin secretion, normoglycemia, upregulation of insulinotropic amino acids in islets, elevated plasma leptin and adiponectin, and diminished gut microbial diversity of the Clostridium leptum group. Together, the findings indicate that autoimmune diabetes is preceded by a state of increased metabolic demands on the islets resulting in elevated insulin secretion and suggest alternative metabolic related pathways as therapeutic targets to prevent diabetes.
    Keywords Biology (General) ; QH301-705.5
    Subject code 570
    Language English
    Publishing date 2011-10-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  6. Article ; Online: Association of lipidome remodeling in the adipocyte membrane with acquired obesity in humans.

    Kirsi H Pietiläinen / Tomasz Róg / Tuulikki Seppänen-Laakso / Sam Virtue / Peddinti Gopalacharyulu / Jing Tang / Sergio Rodriguez-Cuenca / Arkadiusz Maciejewski / Jussi Naukkarinen / Anna-Liisa Ruskeepää / Perttu S Niemelä / Laxman Yetukuri / Chong Yew Tan / Vidya Velagapudi / Sandra Castillo / Heli Nygren / Tuulia Hyötyläinen / Aila Rissanen / Jaakko Kaprio /
    Hannele Yki-Järvinen / Ilpo Vattulainen / Antonio Vidal-Puig / Matej Orešič

    PLoS Biology, Vol 9, Iss 6, p e

    2011  Volume 1000623

    Abstract: Identification of early mechanisms that may lead from obesity towards complications such as metabolic syndrome is of great interest. Here we performed lipidomic analyses of adipose tissue in twin pairs discordant for obesity but still metabolically ... ...

    Abstract Identification of early mechanisms that may lead from obesity towards complications such as metabolic syndrome is of great interest. Here we performed lipidomic analyses of adipose tissue in twin pairs discordant for obesity but still metabolically compensated. In parallel we studied more evolved states of obesity by investigating a separated set of individuals considered to be morbidly obese. Despite lower dietary polyunsaturated fatty acid intake, the obese twin individuals had increased proportions of palmitoleic and arachidonic acids in their adipose tissue, including increased levels of ethanolamine plasmalogens containing arachidonic acid. Information gathered from these experimental groups was used for molecular dynamics simulations of lipid bilayers combined with dependency network analysis of combined clinical, lipidomics, and gene expression data. The simulations suggested that the observed lipid remodeling maintains the biophysical properties of lipid membranes, at the price, however, of increasing their vulnerability to inflammation. Conversely, in morbidly obese subjects, the proportion of plasmalogens containing arachidonic acid in the adipose tissue was markedly decreased. We also show by in vitro Elovl6 knockdown that the lipid network regulating the observed remodeling may be amenable to genetic modulation. Together, our novel approach suggests a physiological mechanism by which adaptation of adipocyte membranes to adipose tissue expansion associates with positive energy balance, potentially leading to higher vulnerability to inflammation in acquired obesity. Further studies will be needed to determine the cause of this effect.
    Keywords Biology (General) ; QH301-705.5
    Subject code 571
    Language English
    Publishing date 2011-06-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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