Search results for "mevalonate"

showing 10 items of 13 documents

Activation of Mevalonate Pathway Via LKB1 is Essential for Stability of Treg Cells

2019

Summary: The function of regulatory T (Treg) cells depends on lipid oxidation. However, the molecular mechanism by which Treg cells maintain lipid metabolism after activation remains elusive. Liver kinase B1 (LKB1) acts as a coordinator by linking cellular metabolism to substrate AMP-activated protein kinase (AMPK). We show that deletion of LKB1 in Treg cells exhibited reduced suppressive activity and developed fatal autoimmune inflammation. Mechanistically, LKB1 induced activation of the mevalonate pathway by upregulating mevalonate genes, which was essential for Treg cell functional competency and stability by inducing Treg cell proliferation and suppressing interferon-gamma and interleuk…

0301 basic medicinecongenital hereditary and neonatal diseases and abnormalitiesGeranylgeranyl pyrophosphateKinaseAMPKFOXP3hemic and immune systemschemical and pharmacologic phenomenaLipid metabolismGeneral Biochemistry Genetics and Molecular BiologyCell biology03 medical and health scienceschemistry.chemical_compound030104 developmental biology0302 clinical medicinelcsh:Biology (General)chemistryLipid oxidationMevalonate pathwayskin and connective tissue diseasesProtein kinase Alcsh:QH301-705.5030217 neurology & neurosurgeryHomeostasisSSRN Electronic Journal
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Geranylgeraniol - a new potential therapeutic approach to bisphosphonate associated osteonecrosis of the jaw.

2010

Bisphosphonate associated osteonecrosis of the jaw (BP-ONJ) is one of the main side effects of bisphosphonate therapy (BPT). To date, there is no effective therapy of the BP-ONJ. Nitrogen-containing bisphosphonates (N-BPs) are particularly able to inhibit pyrophosphate synthase (FPPS) in the mevalonate pathway (MVP). Consequent of decreased synthesis of the metabolite Geranylgeraniol (GGOH) is believed to largely account for the development of BP-ONJ. Negative effect of N-BPs could be shown, resulting in decreased viability and migration capacity of different cell types of hard and soft tissues such as osteoblasts, fibroblast und endothelial cells. Aim of our in vitro study was to demonstra…

Cancer Researchmedicine.medical_specialtyCell typeCellIn Vitro Techniqueschemistry.chemical_compoundGeranylgeraniolmedicineHumansFibroblastBisphosphonate-associated osteonecrosis of the jawMigration AssayOsteoblastsBone Density Conservation AgentsDiphosphonatesbusiness.industryOsteonecrosisEndothelial CellsFibroblastsmedicine.diseaseSurgerymedicine.anatomical_structureOncologychemistryCancer researchMevalonate pathwayOral SurgeryDiterpenesbusinessWound healingJaw DiseasesOral oncology
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Targeting the mevalonate pathway for improved anticancer therapy.

2009

The mevalonate pathway is important for the generation of isoprene moieties thereby providing the basis for the biosynthesis of molecules required for maintaining membrane integrity, steroid production and cell respiration. Additionally, isoprene precursors are indispensable for the prenylation of regulatory proteins such as Ras and Ras-homologous (Rho) GTPases. These low molecular GTP-binding proteins play key roles in numerous signal transduction pathways stimulated upon activation of cell surface receptors by ligand binding. Thus, Ras/Rho proteins eventually regulate cell proliferation, tumor progression and cell death induced by anticancer therapeutics. Lipid modification of Ras/Rho pro…

rho GTP-Binding ProteinsCancer Researchmedicine.medical_treatmentProtein PrenylationMevalonic AcidAntineoplastic AgentsGTPaseModels BiologicalSteroidDrug Delivery SystemsPrenylationCell surface receptorNeoplasmsDrug DiscoverymedicineAnimalsHumansPharmacologyCell DeathDiphosphonatesChemistryCell growthMembrane ProteinsDimethylallyltranstransferaseCell biologyOncologyras ProteinsMevalonate pathwayLipid modificationSignal transductionHydroxymethylglutaryl-CoA Reductase InhibitorsSignal TransductionCurrent cancer drug targets
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Phenotypical and Functional Alteration of γδ T Lymphocytes in COVID-19 Patients: Reversal by Statins

2022

(1) Background: statins have been considered an attractive class of drugs in the pharmacological setting of COVID-19 due to their pleiotropic properties and their use correlates with decreased mortality in hospitalized COVID-19 patients. Furthermore, it is well known that statins, which block the mevalonate pathway, affect γδ T lymphocyte activation. As γδ T cells participate in the inflammatory process of COVID-19, we have investigated the therapeutical potential of statins as a tool to inhibit γδ T cell pro-inflammatory activities; (2) Methods: we harvested peripheral blood mononuclear cells (PBMCs) from COVID-19 patients with mild clinical manifestatio…

T-Lymphocyte SubsetsSARS-CoV-2 infectionLeukocytes Mononuclearmevalonate pathwaystatinHumansCOVID-19γδ T cells; COVID-19; SARS-CoV-2 infection; statin; mevalonate pathwayReceptors Antigen T-Cell gamma-deltaGeneral MedicineHydroxymethylglutaryl-CoA Reductase Inhibitorsγδ T cellsCOVID-19 Drug TreatmentCells; Volume 11; Issue 21; Pages: 3449
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Selenoproteins, cholesterol-lowering drugs, and the consequences: revisiting of the mevalonate pathway.

2004

3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) and peroxisome proliferator-activated receptor alpha activators (fibrates) are the backbone of pharmacologic hypercholesterolemia and dyslipidemia treatment. Many of their clinical effects, however, are still enigmatic. This article describes how a side road of the mevalonate pathway, characterized in recent years, can rationalize a major fraction of these unexplained observations. This side road is the enzymatic isopentenylation of selenocysteine-tRNA([Ser]Sec) (Sec-tRNA), the singular tRNA to decode the unusual amino acid selenocysteine. The functionally indispensable isopentenylation of Sec-tRNA requires a unique interm…

chemistry.chemical_classificationSelenocysteineCoenzyme AHypercholesterolemiaPeroxisome Proliferator-Activated ReceptorsIsopentenyl pyrophosphateMevalonic AcidProteinsBiologyPeroxisomeRNA Transfer Amino AcylAmino acidchemistry.chemical_compoundEnzymechemistryBiochemistryAnimalsMevalonate pathwaySelenoproteinHydroxymethylglutaryl-CoA Reductase InhibitorsCardiology and Cardiovascular MedicineSelenoproteinsTrends in cardiovascular medicine
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Dynamics of Monoterpene Formation in Spike Lavender Plants

2017

The metabolic cross-talk between the mevalonate (MVA) and the methylerythritol phosphate (MEP) pathways was analyzed in spike lavender (Lavandula latifolia Med) on the basis of 13CO2-labelling experiments using wildtype and transgenic plants overexpressing the 3-hydroxy-3-methylglutaryl CoA reductase (HMGR), the first and key enzyme of the MVA pathway. The plants were labelled in the presence of 13CO2 in a gas chamber for controlled pulse and chase periods of time. GC/MS and NMR analysis of 1,8-cineole and camphor, the major monoterpenes present in their essential oil, indicated that the C5-precursors, isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP) of both monoterpenes …

0106 biological sciences0301 basic medicineLavenderEndocrinology Diabetes and MetabolismMonoterpeneLavandula latifolialcsh:QR1-502Reductase01 natural sciencesBiochemistryArticlelcsh:Microbiologylaw.inventionessential oils; isotopologue profiling; lamiaceae; <i>Lavandula latifolia</i>; spike lavender; terpenoid biosynthesis; mevalonate; CO<sub>2</sub>terpenoid biosynthesislamiaceae03 medical and health sciencesCamphorchemistry.chemical_compoundmevalonatelawMolecular Biologyessential oilsEssential oilchemistry.chemical_classificationbiologyChemistrybiology.organism_classificationddc:spike lavender030104 developmental biologyEnzymeisotopologue profilingBiochemistryLamiaceaeCO2Lavandula latifolia010606 plant biology & botanyMetabolites
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Up-regulation of 1-deoxy-D-xylulose-5-phosphate synthase enhances production of essential oils in transgenic spike lavender.

2006

Abstract Spike lavender (Lavandula latifolia) is an aromatic shrub cultivated worldwide for the production of essential oils. The major constituents of these oils are monoterpenes, which are obtained from isopentenyl diphosphate and dimethylallyl diphosphate precursors through the plastidial methylerythritol phosphate (MEP) pathway and/or the cytosolic mevalonate pathway. 1-Deoxy-d-xylulose-5-P synthase (DXS) catalyzes the first step of the MEP pathway. A cDNA coding for the Arabidopsis (Arabidopsis thaliana) DXS was constitutively expressed in spike lavender. Gas chromatography/mass spectrometry analyses revealed that transgenic plants accumulated significantly more essential oils compared…

ChlorophyllPhysiologyTransgeneMolecular Sequence DataLavandula latifoliaPlant ScienceGenetically modified cropslaw.inventionlawGene Expression Regulation PlantTransferasesArabidopsisBotanyGeneticsOils VolatileArabidopsis thalianaEssential oilbiologyATP synthasefood and beveragesbiology.organism_classificationPlants Genetically ModifiedCarotenoidsUp-RegulationPlant LeavesLavandulaBiochemistrybiology.proteinMevalonate pathwayResearch ArticlePlant physiology
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Fluvastatin stabilizes the blood–brain barrier in vitro by nitric oxide-dependent dephosphorylation of myosin light chains

2006

Inhibition of the 3-hydroxy-3-methylglutaryl-coenzyme-A reductase and the downstream mevalonate pathway is in part responsible for the beneficial effects that statins exert on the cardiovascular system. In this study we aimed at analysing the stabilizing effects of fluvastatin on the blood-brain barrier (BBB) integrity, using an in vitro co-culture model of ECV304 and C6, or primary bovine endothelial cells and rat astrocytes. Fluvastatin dose-dependently (1-25 micromol/l) increased barrier integrity as analysed by measurements of transendothelial electrical resistance (TEER). This effect (117.4+/-2.6% at 25 micromol/l) was significantly reduced by the nitric oxide (NO) synthase inhibitor L…

IndolesMyosin Light ChainsMyosin light-chain kinaseGeranylgeranyl pyrophosphatePhosphataseFarnesyl pyrophosphateBiologyNitric OxideBlood–brain barrierAntioxidantsCapillary PermeabilityFatty Acids MonounsaturatedDephosphorylationMiceCellular and Molecular Neurosciencechemistry.chemical_compoundElectric ImpedancemedicineAnimalsDrug InteractionsEnzyme InhibitorsFluvastatinCells CulturedPharmacologyAnalysis of VarianceMicroscopy Confocalomega-N-MethylarginineDose-Response Relationship DrugEndothelial CellsBiological TransportMolecular biologyCoculture TechniquesRatsmedicine.anatomical_structurechemistryBiochemistryBlood-Brain BarrierAstrocytesModels AnimalCattleMevalonate pathwayFluvastatinmedicine.drugNeuropharmacology
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Canakinumab for the Treatment of Autoinflammatory Recurrent Fever Syndromes.

2018

BACKGROUND: Familial Mediterranean fever, mevalonate kinase deficiency (also known as the hyperimmunoglobulinemia D syndrome), and the tumor necrosis factor receptor-associated periodic syndrome (TRAPS) are monogenic autoinflammatory diseases characterized by recurrent fever flares. METHODS: We randomly assigned patients with genetically confirmed colchicine-resistant familial Mediterranean fever, mevalonate kinase deficiency, or TRAPS at the time of a flare to receive 150 mg of canakinumab subcutaneously or placebo every 4 weeks. Patients who did not have a resolution of their flare received an add-on injection of 150 mg of canakinumab. The primary outcome was complete response (resolution…

Male0301 basic medicineInterleukin-1betaFamilial Mediterranean fever0302 clinical medicineMonoclonalChildMedicine(all)Mevalonate kinase deficiencySubcutaneousMedicine (all)Interleukin-1betaAntibodies MonoclonalGeneral MedicineFamilial Mediterranean FeverRecurrent feverChild PreschoolFemaleTumor necrosis factor alphaDrugInflammatory diseases Radboud Institute for Molecular Life Sciences [Radboudumc 5]medicine.drugAdultAdolescentFeverInjections SubcutaneousHereditary Autoinflammatory DiseasesAntibodies Monoclonal HumanizedAdolescent; Adult; Antibodies Monoclonal/administration & dosage; Antibodies Monoclonal/adverse effects; Antibodies Monoclonal/therapeutic use; Child; Child Preschool; Dose-Response Relationship Drug; Double-Blind Method; Familial Mediterranean Fever/drug therapy; Female; Fever/drug therapy; Hereditary Autoinflammatory Diseases/drug therapy; Humans; Injections Subcutaneous; Interleukin-1beta/antagonists & inhibitors; Male; Mevalonate Kinase Deficiency/drug therapy; Young AdultAntibodiesInjectionsDose-Response RelationshipYoung Adult03 medical and health sciencesAll institutes and research themes of the Radboud University Medical CenterDouble-Blind MethodGeneral & Internal MedicinemedicineHumansPreschoolAdolescent; Adult; Antibodies Monoclonal; Child; Child Preschool; Dose-Response Relationship Drug; Double-Blind Method; Familial Mediterranean Fever; Female; Fever; Hereditary Autoinflammatory Diseases; Humans; Injections Subcutaneous; Interleukin-1beta; Male; Mevalonate Kinase Deficiency; Young Adult; Medicine (all)030203 arthritis & rheumatologyDose-Response Relationship Drugbusiness.industryHereditary Autoinflammatory DiseasesHyperimmunoglobulinemia Dmedicine.diseaseCanakinumab030104 developmental biologyImmunologyMevalonate Kinase Deficiencybusiness
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Mevalonate pathway inhibitors affect anticancer drug-induced cell death and DNA damage response of human sarcoma cells

2011

Lovastatin (Lov), bisphosphonates (BP) and metformin (Met) are widely used drugs, having in common that they interfere with the mevalonate pathway (MP). The MP generates isoprene moieties required for the function of regulatory GTPases controlling cell proliferation and survival. Here, we addressed the question whether MP inhibitors interfere with the anti-tumor efficacy of anticancer drugs. We comparatively analyzed the effect of equitoxic doses of Lov, BP and Met on cell viability, cell cycle progression, apoptosis and DNA damage response (DDR) of human osteo- and fibrosarcoma cells exposed to doxorubicin or cisplatin. We found that Lov, BP and Met modulated the anticancer drug sensitivit…

MAPK/ERK pathwayCancer ResearchDNA damageFibrosarcomaBlotting WesternMevalonic AcidAntineoplastic AgentsApoptosisBone NeoplasmsTumor Cells CulturedmedicineHumansDoxorubicinLovastatinRNA MessengerPhosphorylationCell ProliferationCisplatinOsteosarcomaDiphosphonatesbiologyReverse Transcriptase Polymerase Chain ReactionCell growthCell CycleMetforminOncologyDoxorubicinApoptosisHMG-CoA reductasebiology.proteinCancer researchMevalonate pathwayCisplatinTumor Suppressor Protein p53DNA DamageSignal Transductionmedicine.drugCancer Letters
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