157 results on '"factor-kappa-b"'
Search Results
2. TBX3 over-expression causes mammary gland hyperplasia and increases mammary stem-like cells in an inducible transgenic mouse model
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Liu, Jing, Esmailpour, Taraneh, Shang, Xiying, Gulsen, Gultekin, Liu, Andy, and Huang, Taosheng
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breast-cancer patients ,factor-kappa-b ,epithelial-cells ,signaling pathways ,gene family ,mutations ,apoptosis ,proliferation ,repression ,senescence - Published
- 2011
3. Multiple sclerosis is linked to MAPK(ERK) overactivity in microglia
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EXPRESSION ,ACTIVATED PROTEIN-KINASE ,PHOSPHATASE 6 DUSP6 ,IN-VITRO ,DUSP6 ,LMP-1 ,MAPK(ERK) ,UP-REGULATION ,MAPK ,Multiple sclerosis ,FACTOR-KAPPA-B ,MITOGEN ,Microglia ,SIGNALING PATHWAY ,Demyelination ,PROINFLAMMATORY CYTOKINE PRODUCTION - Abstract
Reassessment of published observations in patients with multiple sclerosis (MS) suggests a microglial malfunction due to inappropriate (over)activity of the mitogen-activated protein kinase pathway ERK (MAPK(ERK)). These observations regard biochemistry as well as epigenetics, and all indicate involvement of this pathway. Recent preclinical research on neurodegeneration already pointed towards a role of MAPK pathways, in particular MAPK(ERK). This is important as microglia with overactive MAPK have been identified to disturb local oligodendrocytes which can lead to locoregional demyelination, hallmark of MS. This constitutes a new concept on pathophysiology of MS, besides the prevailing view, i.e., autoimmunity. Acknowledged risk factors for MS, such as EBV infection, hypovitaminosis D, and smoking, all downregulate MAPK(ERK) negative feedback phosphatases that normally regulate MAPK(ERK) activity. Consequently, these factors may contribute to inappropriate MAPK(ERK) overactivity, and thereby to neurodegeneration. Also, MAPK(ERK) overactivity in microglia, as a factor in the pathophysiology of MS, could explain ongoing neurodegeneration in MS patients despite optimized immunosuppressive or immunomodulatory treatment. Currently, for these patients with progressive disease, no effective treatment exists. In such refractory MS, targeting the cause of overactive MAPK(ERK) in microglia merits further investigation as this phenomenon may imply a novel treatment approach.
- Published
- 2021
4. 15-Deoxy-Delta-12,14-prostaglandin J2 modulates pro-labour and pro-inflammatory responses in human myocytes, vaginal and amnion epithelial cells
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Zahirrah BM. Rasheed, Yun S. Lee, Sung H. Kim, Tg Teoh, David A. MacIntyre, Phillip R. Bennett, Lynne Sykes, Majlis Amanah Rakyat (MARA), Malaysian Government Agency, Wellbeing of Women, and Medical Research Council (MRC)
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Lipopolysaccharides ,ACTIVATED RECEPTOR-GAMMA ,Endocrinology, Diabetes and Metabolism ,activator protein (AP)-1 ,Anti-Inflammatory Agents ,15-DEOXY-DELTA(12,14)-PROSTAGLANDIN J(2) ,15-HYDROXYPROSTAGLANDIN DEHYDROGENASE ,15dPGJ2 ,HUMAN GESTATIONAL TISSUES ,Dinoprostone ,prostaglandins ,DIFFERENTIAL EXPRESSION ,Endocrinology & Metabolism ,Mice ,Animals ,Humans ,Amnion ,RNA, Messenger ,Inflammation ,Muscle Cells ,Science & Technology ,Interleukin-6 ,Prostaglandin D2 ,Tumor Necrosis Factor-alpha ,Interleukin-8 ,INTRAUTERINE INFECTION ,Infant, Newborn ,NF-kappa B ,Epithelial Cells ,1103 Clinical Sciences ,preterm labour (PTL) ,nuclear factor- kappa B (NF-kB) ,CYCLOOXYGENASE-2 EXPRESSION ,cytokines ,PROINFLAMMATORY CYTOKINES ,Transcription Factor AP-1 ,FACTOR-KAPPA-B ,Cyclooxygenase 2 ,Premature Birth ,PRETERM LABOR ,Female ,1111 Nutrition and Dietetics ,Life Sciences & Biomedicine ,nuclear factor - kappa B (NF - κB) - Abstract
BackgroundPrematurity is the leading cause of childhood death under the age of five. The aetiology of preterm birth is multifactorial; however, inflammation and infection are the most common causal factors, supporting a potential role for immunomodulation as a therapeutic strategy. 15-Deoxy-Delta-12,14-prostaglandin J2 (15dPGJ2) is an anti-inflammatory prostaglandin and has been shown to delay lipopolysaccharide (LPS) induced preterm labour in mice and improve pup survival. This study explores the immunomodulatory effect of 15dPGJ2 on the transcription factors NF-κB and AP-1, pro-inflammatory cytokines, and contraction associated proteins in human cultured myocytes, vaginal epithelial cell line (VECs) and primary amnion epithelial cells (AECs).MethodsCells were pre-incubated with 32µM of 15dPGJ2 and stimulated with 1ng/mL of IL-1β as an in vitro model of inflammation. Western immunoblotting was used to detect phosphorylated p-65 and phosphorylated c-Jun as markers of NF-κB and AP-1 activation, respectively. mRNA expression of the pro-inflammatory cytokines IL-6, IL-8, and TNF-α was examined, and protein expression of COX-2 and PGE2 were detected by western immunoblotting and ELISA respectively. Myometrial contractility was examined ex-vivo using a myograph.Results15dPGJ2 inhibited IL-1β-induced activation of NF-κB and AP-1, and expression of IL-6, IL-8, TNF-α, COX-2 and PGE2 in myocytes, with no effect on myometrial contractility or cell viability. Despite inhibiting IL-1β-induced activation of NF-κB, expression of IL-6, TNF-α, and COX-2, 15dPGJ2 led to activation of AP-1, increased production of PGE2 and increased cell death in VECs and AECs.ConclusionWe conclude that 15dPGJ2 has differential effects on inflammatory modulation depending on cell type and is therefore unlikely to be a useful therapeutic agent for the prevention of preterm birth.
- Published
- 2022
5. Novel assays monitoring direct glucocorticoid receptor protein activity exhibit high predictive power for ligand activity on endogenous gene targets
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Laura Van Moortel, Jonathan Thommis, Brecht Maertens, An Staes, Dorien Clarisse, Delphine De Sutter, Claude Libert, Onno C. Meijer, Sven Eyckerman, Kris Gevaert, and Karolien De Bosscher
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Pharmacology ,Transcriptional Activation ,Inflammation ,DIMERIZATION ,Drug discovery ,Assay development ,Anti-Inflammatory Agents ,General Medicine ,Glucocorticoid receptor ,Ligands ,SEQUENCE ,MECHANISMS ,FACTOR-KAPPA-B ,AGONIST ,Receptors, Glucocorticoid ,ACTIVATOR PROTEIN-1 ,SEGRAM ,BINDING ,Medicine and Health Sciences ,TRANSCRIPTION ,HEALTH ,PHOSPHORYLATION ,Luciferases ,Glucocorticoids - Abstract
Exogenous glucocorticoids are widely used in the clinic for the treatment of inflammatory disorders and auto-immune diseases. Unfortunately, their use is hampered by many side effects and therapy resistance. Efforts to find more selective glucocorticoid receptor (GR) agonists and modulators (called SEGRAMs) that are able to separate anti-inflammatory effects via gene repression from metabolic effects via gene activation, have been unsuccessful so far. In this study, we characterized a set of functionally diverse GR ligands in A549 cells, first using a panel of luciferase-based reporter gene assays evaluating GR-driven gene activation and gene repression. We expanded this minimal assay set with novel luciferase-based read-outs monitoring GR protein levels, GR dimerization and GR Serine 211 (Ser211) phosphorylation status and compared their outcomes with compound effects on the mRNA levels of known GR target genes in A549 cells and primary hepatocytes. We found that luciferase reporters evaluating GR-driven gene activation and gene repression were not always reliable predictors for effects on endogenous target genes. Remarkably, our novel assay monitoring GR Ser211 phosphorylation levels proved to be the most reliable predictor for compound effects on almost all tested endogenous GR targets, both driven by gene activation and repression. The integration of this novel assay in existing screening platforms running both in academia and industry may therefore boost chances to find novel GR ligands with an actual improved therapeutic benefit.
- Published
- 2022
6. Anticancer secondary metabolites from marine sponges
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Belma Konuklugil, İbrahim Seyda Uras, and Belirlenecek
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Marine sponges ,natural products ,Natural-Products ,Activation ,Cancer-Cells ,Apoptosis ,Biology ,Marine species ,Stellettin B ,cancer treatment ,lcsh:Aquaculture. Fisheries. Angling ,Food and drug administration ,03 medical and health sciences ,High morbidity ,0302 clinical medicine ,lcsh:QH540-549.5 ,marine sponges ,030304 developmental biology ,lcsh:SH1-691 ,0303 health sciences ,Progression ,Factor-Kappa-B ,secondary metabolites ,Drug discovery ,Leiodermatolide ,Cancer treatment ,Potent ,Biochemistry ,In-Vitro ,030220 oncology & carcinogenesis ,lcsh:Ecology ,marine sponge - Abstract
The oceans cover 70% of the Earth’s surface. The marine environment is an important source of secondary metabolites with high biodiversity. Besides other marine species, sponges with a wide range of secondary metabolites are an important potential for drug discovery. Cancer is one of the leading causes of death with high morbidity and mortality. It is very important to discover new therapeutic agents in the treatment of cancer. In recent years, studies on exploring new anticancer compounds are focused on the marine source. In this review, our target is collecting the studies about marine sponges secondary metabolites which have an anticancer effect. Among most of the isolated compounds from sponges and their semisynthetic derivatives, there are three FDA (US Food and Drug Administration) approved compounds and three compounds in clinical phase. Moreover, more than 40 compounds isolated from marine sponges have been tested for anticancer activity in recent 10 years. In conclusion marine sponges secondary metabolites are a promising and important source of the anticancer compounds.
- Published
- 2021
7. Tissue Damage, Not Infection, Triggers Hepatic Unfolded Protein Response in an Experimental Rat Peritonitis Model
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Müllebner, Andrea, Duvigneau, Johanna Catharina, Kozlov, Andrey V., Bauer, Inge, Picker, Olaf, Luís, Andreia, Kames, Martina, Herminghaus, Anna, and Miller, Ingrid
- Subjects
General Medicine ,Endoplasmic-Reticulum Stress ,Ascendens Stent Peritonitis ,Factor-Kappa-B ,Oxidative Stress ,Cecal Ligation ,Sepsis ,Liver ,Activation ,Mitochondrial ,Puncture - Abstract
BackgroundAbdominal surgery is an efficient treatment of intra-abdominal sepsis. Surgical trauma and peritoneal infection lead to the activation of multiple pathological pathways. The liver is particularly susceptible to injury under septic conditions. Liver function is impaired when pathological conditions induce endoplasmic reticulum (ER) stress. ER stress triggers the unfolded protein response (UPR), aiming at restoring ER homeostasis, or inducing cell death. In order to translate basic knowledge on ER function into the clinical setting, we aimed at dissecting the effect of surgery and peritoneal infection on the progression of ER stress/UPR and inflammatory markers in the liver in a clinically relevant experimental animal model.MethodsWistar rats underwent laparotomy followed by colon ascendens stent peritonitis (CASP) or surgery (sham) only. Liver damage (aspartate aminotransferase (AST), alanine aminotransferase (ALT) and De Ritis values), inflammatory and UPR markers were assessed in livers at 24, 48, 72, and 96 h postsurgery. Levels of inflammatory (IL-6, TNF-α, iNOS, and HO-1), UPR (XBP1, GRP78, CHOP), and apoptosis (BAX/Bcl-XL) mRNA were determined by qPCR. Splicing of XBP1 (XBP1s) was analyzed by gel electrophoresis, p-eIF2α and GRP78 protein levels using the western blots.ResultsAspartate aminotransferase levels were elevated 24 h after surgery and thereafter declined with different kinetics in sham and CASP groups. Compared with sham De Ritis ratios were significantly higher in the CASP group, at 48 and 96 h. CASP induced an inflammatory response after 48 h, evidenced by elevated levels of IL-6, TNF-α, iNOS, and HO-1. In contrast, UPR markers XBP1s, p-eIF2α, GRP78, XBP1, and CHOP did not increase in response to infection but paralleled the kinetics of AST and De Ritis ratios. We found that inflammatory markers were predominantly associated with CASP, while UPR markers were associated with surgery. However, in the CASP group, we found a stronger correlation between XBP1s, XBP1 and GRP78 with damage markers, suggesting a synergistic influence of inflammation on UPR in our model.ConclusionOur results indicate that independent mechanisms induce ER stress/UPR and the inflammatory response in the liver. While peritoneal infection predominantly triggers inflammatory responses, the conditions associated with organ damage are predominant triggers of the hepatic UPR.
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- 2022
- Full Text
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8. Estradiol Signaling at the Heart of Folliculogenesis: Its Potential Deregulation in Human Ovarian Pathologies
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Stéphanie Chauvin, Joëlle Cohen-Tannoudji, Céline J. Guigon, Unité de Biologie Fonctionnelle et Adaptative (BFA (UMR_8251 / U1133)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), and ORANGE, Colette
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ER-BETA ,DIFFERENTIAL REGULATION ,QH301-705.5 ,ANTI-MULLERIAN HORMONE ,[SDV]Life Sciences [q-bio] ,Review ,GRANULOSA-CELL TUMORS ,ESTROGEN-RECEPTOR-BETA ,Catalysis ,Inorganic Chemistry ,Ovarian Follicle ,folliculogenesis ,estradiol ,Humans ,Physical and Theoretical Chemistry ,Biology (General) ,Molecular Biology ,QD1-999 ,Spectroscopy ,GENE-EXPRESSION ,estrogen receptors isoforms ,Organic Chemistry ,Ovary ,General Medicine ,IN-VITRO ,FOLLICLE-STIMULATING-HORMONE ,Computer Science Applications ,[SDV] Life Sciences [q-bio] ,FACTOR-KAPPA-B ,Chemistry ,granulosa cells ,polycystic ovary syndrome ,granulosa cell tumors ,Female ,EPIDERMAL-GROWTH-FACTOR ,Signal Transduction - Abstract
International audience; Estradiol (E2) is a major hormone controlling women fertility, in particular folliculogenesis. This steroid, which is locally produced by granulosa cells (GC) within ovarian follicles, controls the development and selection of dominant preovulatory follicles. E2 effects rely on a complex set of nuclear and extra-nuclear signal transduction pathways principally triggered by its nuclear receptors, ER alpha and ER beta. These transcription factors are differentially expressed within follicles, with ER beta being the predominant ER in GC. Several ER beta splice isoforms have been identified and display specific structural features, which greatly complicates the nature of ER beta-mediated E2 signaling. This review aims at providing a concise overview of the main actions of E2 during follicular growth, maturation, and selection in human. It also describes the current understanding of the various roles of ER beta splice isoforms, especially their influence on cell fate. We finally discuss how E2 signaling deregulation could participate in two ovarian pathogeneses characterized by either a follicular arrest, as in polycystic ovary syndrome, or an excess of GC survival and proliferation, leading to granulosa cell tumors. This review emphasizes the need for further research to better understand the molecular basis of E2 signaling throughout folliculogenesis and to improve the efficiency of ovarian-related disease therapies.
- Published
- 2022
9. Rothia mucilaginosa is an anti-inflammatory bacterium in the respiratory tract of patients with chronic lung disease
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Juliana Aizawa, Aurélie Crabbé, Lisa Ostyn, Charlotte Rigauts, Michael M. Tunney, Paul Cos, Lucy D. Burr, Jodie L. Simpson, Heleen Van Acker, Cristina Cigana, Lars Vereecke, Anne Willems, Matthias Govaerts, Tom Coenye, Mozes Sze, Eva Vandeplassche, Geraint B. Rogers, Steven L. Taylor, Alessandra Bragonzi, Sarah K. Sims, and Yves Dondelinger
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Pulmonary and Respiratory Medicine ,MATRIX METALLOPROTEINASES ,LONG-TERM ,PATHOGENESIS ,CYSTIC FIBROSIS BRONCHIECTASIS ,Inflammation ,Cystic fibrosis ,Pathogenesis ,ACTIVATION ,03 medical and health sciences ,0404 agricultural biotechnology ,INFLAMMATION ,medicine ,Medicine and Health Sciences ,030304 developmental biology ,0303 health sciences ,COPD ,Bronchiectasis ,business.industry ,Pharmacology. Therapy ,Biology and Life Sciences ,04 agricultural and veterinary sciences ,AIRWAY MICROBIOTA ,medicine.disease ,COMMUNITY DYNAMICS ,040401 food science ,3. Good health ,FACTOR-KAPPA-B ,EXACERBATIONS ,medicine.anatomical_structure ,Immunology ,Sputum ,Human medicine ,medicine.symptom ,business ,Rothia mucilaginosa ,Respiratory tract - Abstract
BackgroundChronic airway inflammation is the main driver of pathogenesis in respiratory diseases such as severe asthma, chronic obstructive pulmonary disease, cystic fibrosis (CF) and bronchiectasis. While the role of common pathogens in airway inflammation is widely recognised, the influence of other microbiota members is still poorly understood.MethodsWe hypothesised that the lung microbiota contains bacteria with immunomodulatory activity which modulate net levels of immune activation by key respiratory pathogens. Therefore, we assessed the immunomodulatory effect of several members of the lung microbiota frequently reported as present in CF lower respiratory tract samples.ResultsWe show that Rothia mucilaginosa, a common resident of the oral cavity that is also often detectable in the lower airways in chronic disease, has an inhibitory effect on pathogen- or lipopolysaccharide-induced pro-inflammatory responses, in vitro (three-dimensional cell culture model) and in vivo (mouse model). Furthermore, in a cohort of adults with bronchiectasis, the abundance of Rothia species was negatively correlated with pro-inflammatory markers (interleukin (IL)-8 and IL-1β) and matrix metalloproteinase (MMP)-1, MMP-8 and MMP-9 in sputum. Mechanistic studies revealed that R. mucilaginosa inhibits NF-κB pathway activation by reducing the phosphorylation of IκBα and consequently the expression of NF-κB target genes.ConclusionsThese findings indicate that the presence of R. mucilaginosa in the lower airways potentially mitigates inflammation, which could in turn influence the severity and progression of chronic respiratory disorders.
- Published
- 2022
10. Chlamydia pneumoniae Interferes with Macrophage Differentiation and Cell Cycle Regulation to Promote Its Replication
- Author
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Eveliina Taavitsainen-Wahlroos, Ilkka Miettinen, Maarit Ylätalo, Inés Reigada, Kirsi Savijoki, Tuula Anneli Nyman, Leena Hanski, Faculty of Pharmacy, Division of Pharmaceutical Biosciences, Helsinki Institute of Sustainability Science (HELSUS), Explorations of Anti Infectives, Pharmaceutical Design and Discovery group, Department of Food and Nutrition, The Academic Outreach Network, Helsinki One Health (HOH), Divisions of Faculty of Pharmacy, Drug Research Program, and Anti-infectives research
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EXPRESSION ,Article Subject ,Immunology ,SIGNAL-TRANSDUCTION ,PROTEIN ,IN-VITRO ,GAMMA ,UP-REGULATION ,Microbiology ,ENDOTHELIAL-CELLS ,FACTOR-KAPPA-B ,317 Pharmacy ,Virology ,INFECTION ,RESPONSES - Abstract
Chlamydia pneumoniae is a ubiquitous intracellular bacterium which infects humans via the respiratory route. The tendency of C. pneumoniae to persist in monocytes and macrophages is well known, but the underlying host-chlamydial interactions remain elusive. In this work, we have described changes in macrophage intracellular signaling pathways induced by C. pneumoniae infection. Label-free quantitative proteome analysis and pathway analysis tools were used to identify changes in human THP-1-derived macrophages upon C. pneumoniae CV6 infection. At 48-h postinfection, pathways associated to nuclear factor kappa B (NF-kappa B) regulation were stressed, while negative regulation on cell cycle control was prominent at both 48 h and 72 h. Upregulation of S100A8 and S100A9 calcium binding proteins, osteopontin, and purine nucleoside hydrolase, laccase domain containing protein 1 (LACC1) underlined the proinflammatory consequences of the infection, while elevated NF-kappa B2 levels in infected macrophages indicates interaction with the noncanonical NF-kappa B pathway. Infection-induced alteration of cell cycle control was obvious by the downregulation of mini chromosome maintenance (MCM) proteins MCM2-7, and the significance of host cell cycle regulation for C. pneumoniae replication was demonstrated by the ability of a cyclin-dependent kinase (CDK) 4/6 inhibitor Palbociclib to promote C. pneumoniae replication and infectious progeny production. The infection was found to suppress retinoblastoma expression in the macrophages in both protein and mRNA levels, and this change was reverted by treatment with a histone deacetylase inhibitor. The epigenetic suppression of retinoblastoma, along with upregulation of S100A8 and S100A9, indicate host cell changes associated with myeloid-derived suppressor cell (MDSC) phenotype.
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- 2022
- Full Text
- View/download PDF
11. Resveratrol supplementation at old age reverts changes associated with aging in inflammatory, oxidative and apoptotic markers in rat heart
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Elena Vara, Ricardo Gredilla, Jesús Ángel Fernández-Tresguerres, Rubén Torregrosa-Muñumer, STEMM - Stem Cells and Metabolism Research Program, and Research Programs Unit
- Subjects
Male ,0301 basic medicine ,Aging ,STRESS ,Medicine (miscellaneous) ,Apoptosis ,Pharmacology ,Resveratrol ,medicine.disease_cause ,Antioxidants ,chemistry.chemical_compound ,0302 clinical medicine ,Stilbenes ,Endothelial dysfunction ,skin and connective tissue diseases ,GENE-EXPRESSION ,SIRT1 ACTIVATION ,Nutrition and Dietetics ,CARDIOVASCULAR HEALTH ,biology ,food and beverages ,Heart ,3. Good health ,Nitric oxide synthase ,FACTOR-KAPPA-B ,medicine.symptom ,3143 Nutrition ,CARDIAC DYSFUNCTION ,Programmed cell death ,030209 endocrinology & metabolism ,Inflammation ,Oxidative phosphorylation ,03 medical and health sciences ,TERM CALORIC RESTRICTION ,Oxidation ,medicine ,Animals ,NITRIC-OXIDE SYNTHASE ,030109 nutrition & dietetics ,business.industry ,medicine.disease ,Rats ,Oxidative Stress ,chemistry ,CELL-DEATH ,Dietary Supplements ,ENDOTHELIAL DYSFUNCTION ,biology.protein ,business ,Oxidative stress - Abstract
Purpose Aging is known to play a critical role in the etiopathogenesis of several diseases. Among them, cardiovascular disorders are especially relevant since they are becoming the first cause of death in western countries. Resveratrol is a polyphenolic compound that has been shown to exert beneficial effects at different levels, including neuronal and cardiovascular protection. Those effects of resveratrol are related, at least in part, to its antioxidant and anti-inflammatory properties. In the current investigation we were interested in exploring whether the positive effects of resveratrol at cardiac level were taking place even when the supplementation started in already old animals. Methods Old male rats were supplemented with resveratrol during 10 weeks. Using RT-PCR, we analyzed the effects of resveratrol supplementation on the expression of different genes related to inflammation, oxidative stress and apoptosis in rat heart. Results Resveratrol reverted age-related changes in inflammatory, oxidative and apoptotic markers in the rat heart. Among others, the expression of two major inflammatory markers, INF-gamma and TNF-alpha and two oxidative markers, heme oxygenase-1 and nitric oxide synthase, were increased with aging, and resveratrol supplementation reduced the level of some of these to those observed in the heart of young animals. Moreover, age-related changes in apoptotic markers in rat heart tend to be also reverted by resveratrol treatment. Conclusion Our results suggest that resveratrol might exert beneficial effects as an anti-aging compound to revert age-related changes in cardiac function.
- Published
- 2021
12. Multiple sclerosis is linked to MAPKERK overactivity in microglia
- Author
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Jon D. Laman, Bert A. 't Hart, Jolande Bolk, and George J.A. ten Bosch
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0301 basic medicine ,MAPK/ERK pathway ,Review ,MAPK(ERK) ,UP-REGULATION ,medicine.disease_cause ,Autoimmunity ,0302 clinical medicine ,Risk Factors ,Drug Discovery ,PROINFLAMMATORY CYTOKINE PRODUCTION ,Genetics (clinical) ,Microglia ,ACTIVATED PROTEIN-KINASE ,PHOSPHATASE 6 DUSP6 ,Neurodegeneration ,Neurodegenerative Diseases ,LMP-1 ,MAPKERK ,Multiple sclerosis ,Pathophysiology ,FACTOR-KAPPA-B ,medicine.anatomical_structure ,Phenotype ,MITOGEN ,Molecular Medicine ,SIGNALING PATHWAY ,Disease Susceptibility ,Signal transduction ,Demyelination ,Mitogen-Activated Protein Kinases ,EXPRESSION ,Multiple Sclerosis ,MAP Kinase Signaling System ,DUSP6 ,03 medical and health sciences ,medicine ,Animals ,Humans ,Genetic Predisposition to Disease ,Alleles ,business.industry ,IN-VITRO ,medicine.disease ,MAPK ,Molecular medicine ,Disease Models, Animal ,030104 developmental biology ,Mutation ,business ,Neuroscience ,030217 neurology & neurosurgery ,Demyelinating Diseases - Abstract
Reassessment of published observations in patients with multiple sclerosis (MS) suggests a microglial malfunction due to inappropriate (over)activity of the mitogen-activated protein kinase pathway ERK (MAPKERK). These observations regard biochemistry as well as epigenetics, and all indicate involvement of this pathway. Recent preclinical research on neurodegeneration already pointed towards a role of MAPK pathways, in particular MAPKERK. This is important as microglia with overactive MAPK have been identified to disturb local oligodendrocytes which can lead to locoregional demyelination, hallmark of MS. This constitutes a new concept on pathophysiology of MS, besides the prevailing view, i.e., autoimmunity. Acknowledged risk factors for MS, such as EBV infection, hypovitaminosis D, and smoking, all downregulate MAPKERKnegative feedback phosphatases that normally regulate MAPKERKactivity. Consequently, these factors may contribute to inappropriate MAPKERKoveractivity, and thereby to neurodegeneration. Also, MAPKERKoveractivity in microglia, as a factor in the pathophysiology of MS, could explain ongoing neurodegeneration in MS patients despite optimized immunosuppressive or immunomodulatory treatment. Currently, for these patients with progressive disease, no effective treatment exists. In such refractory MS, targeting the cause of overactive MAPKERKin microglia merits further investigation as this phenomenon may imply a novel treatment approach.
- Published
- 2021
13. Lung Cancer Management with Silibinin: A Historical and Translational Perspective
- Author
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Universitat Rovira i Virgili, Verdura, Sara; Cuyas, Elisabet; Ruiz-Torres, Veronica; Micol, Vicente; Joven, Jorge; Bosch-Barrera, Joaquim; Menendez, Javier A., Universitat Rovira i Virgili, and Verdura, Sara; Cuyas, Elisabet; Ruiz-Torres, Veronica; Micol, Vicente; Joven, Jorge; Bosch-Barrera, Joaquim; Menendez, Javier A.
- Abstract
The flavonolignan silibinin, the major bioactive component of the silymarin extract of Silybum marianum (milk thistle) seeds, is gaining traction as a novel anti-cancer therapeutic. Here, we review the historical developments that have laid the groundwork for the evaluation of silibinin as a chemopreventive and therapeutic agent in human lung cancer, including translational insights into its mechanism of action to control the aggressive behavior of lung carcinoma subtypes prone to metastasis. First, we summarize the evidence from chemically induced primary lung tumors supporting a role for silibinin in lung cancer prevention. Second, we reassess the preclinical and clinical evidence on the effectiveness of silibinin against drug resistance and brain metastasis traits of lung carcinomas. Third, we revisit the transcription factor STAT3 as a central tumor-cell intrinsic and microenvironmental target of silibinin in primary lung tumors and brain metastasis. Finally, by unraveling the selective vulnerability of silibinin-treated tumor cells to drugs using CRISPR-based chemosensitivity screenings (e.g., the hexosamine biosynthesis pathway inhibitor azaserine), we illustrate how the therapeutic use of silibinin against targetable weaknesses might be capitalized in specific lung cancer subtypes (e.g., KRAS/STK11 co-mutant tumors). Forthcoming studies should take up the challenge of developing silibinin and/or next-generation silibinin derivatives as novel lung cancer-preventive and therapeutic biomolecules.
- Published
- 2021
14. A polymorphism in the promoter of FRAS1 is a candidate SNP associated with metastatic prostate cancer
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Anis A. Hamid, Karina Dalsgaard Sørensen, Timothy R. Rebbeck, Mark Pomerantz, Jong Y. Park, Matthew L. Freedman, Sarah C. Markt, Sonja I. Berndt, Ana Vega, Ros Eeles, Kristina M. Jordahl, Christopher Sweeney, Victoria Wang, Daniela Börnigen, Lorelei A. Mucci, Gwo-Shu Mary Lee, Huma Q. Rana, Nawaid Usmani, Milan S. Geybels, Janet L. Stanford, Frank Claessens, Kathryn L. Penney, Curtis Huttenhower, Travis Gerke, RS: GROW - R1 - Prevention, and Epidemiologie
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0301 basic medicine ,Oncology ,Male ,Genome-wide association study ,Disease ,VARIANTS ,Cohort Studies ,Prostate cancer ,single nucleotide polymorphisms ,0302 clinical medicine ,Medicine ,Promoter Regions, Genetic ,Aged, 80 and over ,RISK ,Extracellular Matrix Proteins ,MEN ,Middle Aged ,STATISTICS ,FACTOR-KAPPA-B ,African ancestry ,030220 oncology & carcinogenesis ,SURVIVAL ,nuclear factor kappa B ,RADIOTHERAPY ,SNPs ,Adult ,medicine.medical_specialty ,SUSCEPTIBILITY LOCI ,Urology ,Single-nucleotide polymorphism ,Polymorphism, Single Nucleotide ,Article ,03 medical and health sciences ,Internal medicine ,SNP ,Humans ,GENOME-WIDE ASSOCIATION ,Genetic Association Studies ,Aged ,business.industry ,MORTALITY ,Cancer ,Prostatic Neoplasms ,Odds ratio ,medicine.disease ,Minor allele frequency ,030104 developmental biology ,ANDROGEN DEPRIVATION ,business ,Follow-Up Studies ,Genome-Wide Association Study - Abstract
BACKGROUND: Inflammation and one of its mediators, NF-kappa B (NFκB), have been implicated in prostate cancer carcinogenesis. We assessed whether germline polymorphisms associated with NFκB are associated with the risk of developing lethal disease (metastases or death from prostate cancer).METHODS: Using a Bayesian approach leveraging NFκB biology with integration of publicly available datasets we used a previously defined genome-wide functional association network specific to NFκB and lethal prostate cancer. A dense-module-searching method identified modules enriched with significant genes from a genome-wide association study (GWAS) study in a discovery data set, Physicians' Health Study and Health Professionals Follow-up Study (PHS/HPFS). The top 48 candidate single nucleotide polymorphisms (SNPs) from the dense-module-searching method were then assessed in an independent prostate cancer cohort and the one SNP reproducibly associated with lethality was tested in a third cohort. Logistic regression models evaluated the association between each SNP and lethal prostate cancer. The candidate SNP was assessed for association with lethal prostate cancer in 6 of 28 studies in the prostate cancer association group to investigate cancer associated alterations in the genome (PRACTICAL) Consortium where there was some medical record review for death ascertainment which also had SNP data from the ONCOARRAY platform. All men self-identified as Caucasian.RESULTS: The rs1910301 SNP which was reproducibly associated with lethal disease was nominally associated with lethal disease (odds ratio [OR] = 1.40; p = .02) in the discovery cohort and the minor allele was also associated with lethal disease in two independent cohorts (OR = 1.35; p = .04 and OR = 1.35; p = .07). Fixed effects meta-analysis of all three cohorts found an association: OR = 1.37 (95% confidence interval [CI]: 1.15-1.62, p = .0003). This SNP is in the promoter region of FRAS1, a gene involved in epidermal-basement membrane adhesion and is present at a higher frequency in men with African ancestry. No association was found in the subset of studies from the PRACTICAL consortium studies which had a total of 106 deaths out total of 3263 patients and a median follow-up of 4.4 years.CONCLUSIONS: Through its connection with the NFκB pathway, a candidate SNP with a higher frequency in men of African ancestry without cancer was found to be associated with lethal prostate cancer across three well-annotated independent cohorts of Caucasian men.
- Published
- 2021
15. A comparative study of the in vitro enzyme inhibitory and antioxidant activities of Butea monosperma (Lam.) Taub. and Sesbania grandiflora (L.) Poiret from Pakistan: New sources of natural products for public health problems
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Waqas Khan Kayani, João Varela, Luísa Barreira, S.A. Boukhari, Luísa Custódio, N. da Rosa Neng, Haroon Ahmed, José M.F. Nogueira, Saira Asif, Gokhan Zengin, Khawaja Shafique Ahmad, M. Baessa, Tamára Santos, Catarina Pereira, Adriano Mollica, and Maria João Rodrigues
- Subjects
0106 biological sciences ,Metal chelating activity ,DPPH ,Decoction ,Flowers ,Plant Science ,Sesbania grandiflora ,Antimicrobial activity ,01 natural sciences ,Extracts ,chemistry.chemical_compound ,Phenolic composition ,Biological-activities ,food ,Syringic acid ,Butea ,Factor-kappa-B ,ABTS ,Neochlorogenic acid ,biology ,food.dish ,Traditional medicine ,Chemistry ,Protein ,biology.organism_classification ,3. Good health ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,Oxidative stress ,Skin hyperpigmentation ,Cell-line ,010606 plant biology & botany - Abstract
Infusions, decoctions and tinctures were prepared from flowers of Butea monosperma (Lam.) Taub. and Sesbania grandiflora (L.) Poiret and evaluated for in vitro inhibition of enzymes implicated on the onset of neurological diseases (acetylcholinesterase: AChE and butyrylcholinesterase: BuChE), diabetes (alpha-glucosidase and alpha-amylase), obesity (lipase) and skin hyperpigmentation (tyrosinase). Extracts were also appraised for radical scavenging activity (RSA) on 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2'-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) radicals, and for metal chelating activity on copper and iron ions. Samples were evaluated for their total contents in different phenolics groups by spectrophotometric methods, for phenolic profile by high performance liquid chromatography e diode array detection (HPLC-DAD) and for mineral contents by microwave plasma-atomic emission spectrometry (MP-AE). Regarding B. monosperma, the tincture allowed for a moderate inhibition of AChE, the decoction was able to inhibit alpha-glucosidase and no activity was observed towards BuChE, alpha-amylase or lipase. All extracts had a low or moderate inhibition towards tyrosinase, and significant RSA and metal chelating potential. As for S. grandiflora, only the decoction inhibited AChE, none of the extracts was able to inhibit BuChE, all samples inhibited alpha-glucosidase and infusions and decoctions had similar inhibitory properties towards alpha-amylase. None of the extracts was active against lipase, but all were able to inhibit tyrosinase. Extracts had also significant RSA, moderate copper chelation and decoctions had the capacity to chelate iron. The most abundant macroelements in both species were potassium and calcium, while iron was the prevalent microelement, especially in B. monosperma. Both species had significant levels of phenolic compounds, and the main components in decoctions and infusions of B. monosperma were syringic and salicylic acids, while the major compound identified in tinctures was the flavonoid luteolin-7-O-glucoside. In S. grandiflora the most abundant were chlorogenic and neochlorogenic acids and catechin hydrate. Molecular docking studies on the most abundant molecules in S. grandiflora, (+)-catechin, chlorogenic acid and neochlorogenic acid, indicate that these compounds are able to dock to alpha-glucosidase in a similar manner than acarbose. Our results suggest that flowers of both species are a promising source of high value-added compounds with enzyme inhibitory and antioxidant properties. (c) 2018 SAAB. Published by Elsevier B.V. All rights reserved. Foundation for Science and Technology (FCT)Portuguese Foundation for Science and Technology Portuguese National Budget [CCMAR/Multi/04326] FCT Investigator Programme [IF/00049/2012] FCTPortuguese Foundation for Science and Technology [SFRH/BD/94407/2013, SFRH/BD/116604/2016]
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- 2019
16. Metformin inhibits polyphosphate-induced hyper-permeability and inflammation
- Author
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Saeedeh Mehraban, Milad Hashemzehi, Reyhaneh Behnam-Rassouli, Mohammad-Hassan Arjmand, Farzad Rahmani, Maryam Fakhraie, Seyed Mahdi Hassanian, Mikhail Ryzhikov, Sayyed-Hadi Sayyed-Hosseinian, Farnaz Barneh, Mohieddin Jafari, Najmeh Jaberi, Mohammad Shabani, Seyede leili Adel barkhordar, Majid Khazaei, Gordon A. Ferns, Fatemeh Ariakia, Fereshteh Asgharzadeh, Amir Avan, Atena Soleimani, Research Program in Systems Oncology, and Research Programs Unit
- Subjects
Male ,Anti-Inflammatory Agents ,Vascular permeability ,030204 cardiovascular system & hematology ,VASCULAR-PERMEABILITY ,COMPLEMENT ,ACTIVATION ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,AMP-Activated Protein Kinase Kinases ,Cell Movement ,Polyphosphates ,Immunology and Allergy ,0303 health sciences ,Factor XII ,Mice, Inbred BALB C ,MOLECULAR-MECHANISMS ,Chemistry ,TOR Serine-Threonine Kinases ,PLATELETS ,Metformin ,3. Good health ,FACTOR-KAPPA-B ,317 Pharmacy ,medicine.symptom ,Oxidation-Reduction ,medicine.drug ,Signal Transduction ,Immunology ,COAGULATION ,Bradykinin ,Inflammation ,Capillary Permeability ,03 medical and health sciences ,Sepsis ,medicine ,Human Umbilical Vein Endothelial Cells ,Animals ,Humans ,Platelet activation ,PI3K/AKT/mTOR pathway ,030304 developmental biology ,Pharmacology ,AMPK ,digestive system diseases ,INORGANIC POLYPHOSPHATE ,Disease Models, Animal ,Oxidative Stress ,MAMMALIAN TARGET ,Cancer research ,AMPK signaling ,RESPONSES - Abstract
Circulating inflammatory factor inorganic polyphosphate (polyP) released from activated platelets could enhance factor XII and bradykinin resulted in increased capillary leakage and vascular permeability. PolyP induce inflammatory responses through mTOR pathway in endothelial cells, which is being reported in several diseases including atherosclerosis, thrombosis, sepsis, and cancer. Systems and molecular biology approaches were used to explore the regulatory role of the AMPK activator, metformin, on polyP-induced hyper-permeability in different organs in three different models of polyP-induced hyper-permeability including local, systemic shortand systemic long-term approaches in murine models. Our results showed that polyP disrupts endothelial barrier integrity in skin, liver, kidney, brain, heart, and lung in all three study models and metformin abrogates the disruptive effect of polyP. We also showed that activation of AMPK signaling pathway, regulation of oxidant/ anti-oxidant balance, as well as decrease in inflammatory cell infiltration constitute a set of molecular mechanisms through which metformin elicits it's protective responses against polyP-induced hyper-permeability. These results support the clinical values of AMPK activators including the FDA-approved metformin in attenuating vascular damage in polyP-associated inflammatory diseases.
- Published
- 2021
17. Effects of aleurone supplementation on glucose-insulin metabolism and gut microbiome in untrained healthy horses
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Berit Boshuizen, Carmen Vidal Moreno de Vega, Lorie De Maré, Constance de Meeûs, Jean Eduardo de Oliveira, Guilherme Hosotani, Yannick Gansemans, Dieter Deforce, Filip Van Nieuwerburgh, and Catherine Delesalle
- Subjects
medicine.medical_specialty ,HIGH-FAT DIET ,030309 nutrition & dietetics ,medicine.medical_treatment ,Firmicutes ,03 medical and health sciences ,Downregulation and upregulation ,Internal medicine ,Aleurone ,medicine ,insulin sensitivity ,betaine ,Microbiome ,Veterinary Sciences ,WHOLE-GRAIN WHEAT ,030304 developmental biology ,Original Research ,equine ,0303 health sciences ,lcsh:Veterinary medicine ,General Veterinary ,biology ,Bran ,Bacteroidetes ,Prebiotic ,Insulin ,ANTIOXIDANT PROPERTIES ,biology.organism_classification ,gut health ,PHENOLIC-ACIDS ,FACTOR-KAPPA-B ,Endocrinology ,Postprandial ,prebiotic ,POSTPRANDIAL GLUCOSE ,FECAL MICROBIOTA ,BRAN ,lcsh:SF600-1100 ,BETAINE SUPPLEMENTATION ,Veterinary Science ,Roseburia ,FERULIC ACID ,ferulic acid - Abstract
Aleurone, a layer of the bran fraction, is deemed to be responsible for the positive health effects associated with the consumption of whole-grain products. Studies on rodents, pigs, and humans report beneficial effects of aleurone in five main areas: the reduction of oxidative stress, immunomodulatory effects, modulation of energy management, digestive health, and the storage of vitamins and minerals. Our study is the first aleurone supplementation study performed in horses. The aim of this study was to investigate the effect of an increase in the dose levels of aleurone on the postprandial glucose-insulin metabolism and the gut microbiome in untrained healthy horses. Seven adult Standardbred horses were supplemented with four different dose levels of aleurone (50, 100, 200, and 400 g/day for 1 week) by using a Latin square model with a 1-week wash out in between doses. On day 7 of each supplementation week, postprandial blood glucose-insulin was measured and fecal samples were collected. 16S ribosomal RNA (rRNA) gene sequencing was performed and QIIME2 software was used for microbiome analysis. Microbial community function was assessed by using the predictive metagenome analysis tool Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt) and using the Metacyc database of metabolic pathways. The relative abundancies of a pathway were analyzed by using analysis of composition of microbiomes (ANCOM) in R. There was a significant dose-dependent increase in the postprandial time to peak of glucose (p = 0.030), a significant delay in the time to peak of insulin (p = 0.025), and a significant decrease in both the insulin peak level (p = 0.049) and insulin area under the curve (AUC) (p = 0.019) with increasing dose levels of aleurone, with a consideration of 200 g being the lowest significant dose. Alpha diversity and beta diversity of the fecal microbiome showed no significant changes. Aleurone significantly decreased the relative abundance of the genera Roseburia, Shuttleworthia, Anaerostipes, Faecalibacter, and Succinovibrionaceae. The most pronounced changes in the relative abundance at phyla level were seen in Firmicutes and Verrucomicrobia (downregulation) and Bacteroidetes and Spirochaetes (upregulation). The PICRUSt analysis shows that aleurone induces a downregulation of the degradation of L-glutamate and taurine and an upregulation of the three consecutive pathways of the phospholipid membrane synthesis of the Archaea domain. The results of this study suggest a multimodal effect of aleurone on glucose-insulin metabolism, which is most likely to be caused by its effect on feed texture and subsequent digestive processing; and a synergistic effect of individual aleurone components on the glucose-insulin metabolism and microbiome composition and function.
- Published
- 2021
18. Peripheral inflammation preceeding ischemia impairs neuronal survival through mechanisms involving miR-127 in aged animals
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Loppi, Sanna, Korhonen, Paula, Bouvy-Liivrand, Maria, Caligola, Simone, Turunen, Tiia A, Turunen, Mikko P, Hernandez de Sande, Ana, Kołosowska, Natalia, Scoyni, Flavia, Rosell, Anna, García-Berrocoso, Teresa, Lemarchant, Sighild, Dhungana, Hiramani, Montaner, Joan, Koistinaho, Jari, Kanninen, Katja M, Kaikkonen, Minna U, Giugno, Rosalba, Heinäniemi, Merja, Malm, Tarja, and Neuroscience Center
- Subjects
Male ,EXPRESSION ,Original Paper ,microRNA ,aging ,26S PROTEASOME ,3112 Neurosciences ,Original Articles ,sequencing ,stroke ,ASTROCYTES ,DISEASE ,Brain Ischemia ,BRAIN-DAMAGE ,Disease Models, Animal ,MicroRNAs ,FACTOR-KAPPA-B ,REDUCTION ,MICE ,proteasome ,inflammation ,INJURY ,Animals ,Humans - Abstract
Ischemic stroke, the third leading cause of death in the Western world, affects mainly the elderly and is strongly associated with comorbid conditions such as atherosclerosis or diabetes, which are pathologically characterized by increased inflammation and are known to influence the outcome of stroke. Stroke incidence peaks during influenza seasons, and patients suffering from infections such as pneumonia prior to stroke exhibit a worse stroke outcome. Earlier studies have shown that comorbidities aggravate the outcome of stroke, yet the mediators of this phenomenon remain obscure. Here, we show that acute peripheral inflammation aggravates stroke‐induced neuronal damage and motor deficits specifically in aged mice. This is associated with increased levels of plasma proinflammatory cytokines, rather than with an increase of inflammatory mediators in the affected brain parenchyma. Nascent transcriptomics data with mature microRNA sequencing were used to identify the neuron‐specific miRNome, in order to decipher dysregulated miRNAs in the brains of aged animals with stroke and co‐existing inflammation. We pinpoint a previously uninvestigated miRNA in the brain, miR‐127, that is highly neuronal, to be associated with increased cell death in the aged, LPS‐injected ischemic mice. Target prediction tools indicate that miR‐127 interacts with several basally expressed neuronal genes, and of these we verify miR‐127 binding to Psmd3. Finally, we report reduced expression of miR‐127 in human stroke brains. Our results underline the impact of peripheral inflammation on the outcome of stroke in aged subjects and pinpoint molecular targets for restoring endogenous neuronal capacity to combat ischemic stroke., Peripheral inflammation preceeding ischemic stroke impairs neuronal survival specifically in the elderly. This increased vulnerability is associated with downregulation of the expression of miR‐127, in both animals and humans. Our results reveal novel molecular targets for treating ischemic stroke, and underline the impact of peripheral inflammation on the outcome of stroke in aged subjects.
- Published
- 2021
19. Short-Chain Fatty Acids (Except Hexanoic Acid) Lower NF-kB Transactivation, Which Rescues Inflammation-Induced Decreased Apolipoprotein A-I Transcription in HepG2 Cells
- Author
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Herman E. Popeijus, Fatma B. A. Mokhtar, Jehad Z. Tayyeb, Jogchum Plat, Maurice C. J. M. Konings, Ronald P. Mensink, Nutrition and Movement Sciences, and RS: NUTRIM - R1 - Obesity, diabetes and cardiovascular health
- Subjects
0301 basic medicine ,SCFAs ,Apolipoprotein B ,Proto-Oncogene Proteins c-jun ,PPARα ,NF-κB ,lcsh:Chemistry ,ACTIVATION ,chemistry.chemical_compound ,Transactivation ,0302 clinical medicine ,Transcription (biology) ,PPAR-ALPHA ,polycyclic compounds ,lcsh:QH301-705.5 ,Spectroscopy ,GENE-EXPRESSION ,Kelch-Like ECH-Associated Protein 1 ,biology ,Chemistry ,ApoA-I ,GUT MICROBIOTA ,NF-kappa B ,Hep G2 Cells ,General Medicine ,Computer Science Applications ,Butyrates ,FACTOR-KAPPA-B ,030220 oncology & carcinogenesis ,I-kappa B Proteins ,lipids (amino acids, peptides, and proteins) ,medicine.symptom ,Proto-Oncogene Proteins c-fos ,Transcriptional Activation ,medicine.medical_specialty ,INHIBITION ,Inflammation ,Butyrate ,Article ,Catalysis ,Proinflammatory cytokine ,Inorganic Chemistry ,03 medical and health sciences ,Carnitine palmitoyltransferase 1 ,BUTYRATE ,Internal medicine ,Valerates ,medicine ,Humans ,PPAR alpha ,Physical and Theoretical Chemistry ,Caproates ,Molecular Biology ,Apolipoprotein A-I ,Carnitine O-Palmitoyltransferase ,Interleukin-8 ,Organic Chemistry ,nutritional and metabolic diseases ,Fatty Acids, Volatile ,030104 developmental biology ,Endocrinology ,lcsh:Biology (General) ,lcsh:QD1-999 ,inflammation ,biology.protein ,Propionates - Abstract
Concentrations of apolipoprotein A-I (ApoA-I) decrease during inflammation, which may lead to dysfunctional ApoA-I-poor high-density lipoprotein (HDL) particles, and as such, elevate cardiovascular risk. Therefore, rescuing ApoA-I concentrations, especially during inflammation, seems beneficial. Recently, short-chain fatty acids (SCFAs) have received more attention as a strategy in reversing atherosclerosis. We here evaluated the effects of SCFAs on inflammatory pathways in relation to ApoA-I transcription. SCFAs dose&ndash, response studies were performed in the presence and absence of inflammatory cytokines. ApoA-I and interleukin 8 (IL-8) mRNA expression were analyzed using qPCR and ELISA, respectively. To study underlying mechanisms, nuclear factor kappa B (NF-&kappa, B) transactivation and changes in mRNA expressions of the genes targets of bromodomain and extra-terminal (BET) inhibition, peroxisome proliferator-activated receptor-alpha (PPAR&alpha, ) transactivation and activator protein 1 (AP-1) pathway were analyzed. SCFAs (except hexanoic acid) increased ApoA-I mRNA transcription in both normal and inflammatory conditions and lowered IL-8 mRNA expression. This anti-inflammatory effect of SCFAs was confirmed by inhibition of NF-&kappa, B transactivation. Moreover, butyric acid increased carnitine palmitoyltransferase 1 (CPT1), PPAR&alpha, target gene, mRNA transcription in both conditions, and there was a negative correlation between CPT1 and NF-&kappa, B. Therefore, PPAR&alpha, transactivation is probably involved in the anti-inflammatory effects of SCFAs, which rescues ApoA-I transcription. In conclusion, propionate, butyrate and valerate elicit anti-inflammatory effects which might rescue ApoA-I transcription in inflammatory conditions via PPAR&alpha, transactivation mediated NF-&kappa, B inhibition.
- Published
- 2020
20. Neutrophil microvesicles drive atherosclerosis by delivering miR-155 to atheroprone endothelium
- Author
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Victoria Ridger, Chiara Recarti, Marwa Mahmoud, Andreas Schober, Amanda Burnett, Merete Long, Ingrid Gomez, Ben Ward, Jessica Johnston, Marc A. M. J. van Zandvoort, Sheila E. Francis, Siôn A Parry, Paul G. Hellewell, Endre Kiss-Toth, Mark P. Ariaans, Celine Souilhol, Le Anh Luong, Rohit Bazaz, Laura West, Rachel M Woods, Birke J. Benedikter, Chiara Niespolo, Paul C. Evans, Carl J. Hulston, Med Microbiol, Infect Dis & Infect Prev, RS: NUTRIM - R2 - Liver and digestive health, RS: Carim - B06 Imaging, and Moleculaire Celbiologie
- Subjects
0301 basic medicine ,Mice, Knockout, ApoE ,Neutrophils ,General Physics and Astronomy ,030204 cardiovascular system & hematology ,PATHWAY ,Pathogenesis ,Mice ,0302 clinical medicine ,Macrophage ,Platelet ,Lymphocytes ,lcsh:Science ,Multidisciplinary ,Smooth-muscle-cells ,NF-kappa B ,ASSOCIATION ,Plaque, Atherosclerotic ,3. Good health ,FACTOR-KAPPA-B ,medicine.anatomical_structure ,miRNAs ,medicine.symptom ,EXPRESSION ,Adhesion molecule ,Endothelium ,Cell-derived microparticles ,Science ,Activation ,Inflammation ,Diet, High-Fat ,Article ,General Biochemistry, Genetics and Molecular Biology ,miR-155 ,03 medical and health sciences ,microRNA ,medicine ,Animals ,Humans ,business.industry ,Macrophages ,Endothelial Cells ,General Chemistry ,Atherosclerosis ,Microvesicles ,Disease Models, Animal ,MicroRNAs ,030104 developmental biology ,Gene Expression Regulation ,Cancer research ,lcsh:Q ,business - Abstract
Neutrophils are implicated in the pathogenesis of atherosclerosis but are seldom detected in atherosclerotic plaques. We investigated whether neutrophil-derived microvesicles may influence arterial pathophysiology. Here we report that levels of circulating neutrophil microvesicles are enhanced by exposure to a high fat diet, a known risk factor for atherosclerosis. Neutrophil microvesicles accumulate at disease-prone regions of arteries exposed to disturbed flow patterns, and promote vascular inflammation and atherosclerosis in a murine model. Using cultured endothelial cells exposed to disturbed flow, we demonstrate that neutrophil microvesicles promote inflammatory gene expression by delivering miR-155, enhancing NF-κB activation. Similarly, neutrophil microvesicles increase miR-155 and enhance NF-κB at disease-prone sites of disturbed flow in vivo. Enhancement of atherosclerotic plaque formation and increase in macrophage content by neutrophil microvesicles is dependent on miR-155. We conclude that neutrophils contribute to vascular inflammation and atherogenesis through delivery of microvesicles carrying miR-155 to disease-prone regions., The role of neutrophils in the development of atherosclerosis has long been an enigma, with few neutrophils detected within the plaque. Here, the authors show that microvesicles released from neutrophils increase vascular inflammation and enhance atherosclerotic plaque formation through delivery of miR-155.
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- 2020
21. Latest perspectives on glucocorticoid-induced apoptosis and resistance in lymphoid malignancies
- Author
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Dorien Clarisse, Karolien De Bosscher, and Fritz Offner
- Subjects
0301 basic medicine ,Cancer Research ,Cell Survival ,Apoptosis ,BCL-2 FAMILY PROTEINS ,Glucocorticoid receptor ,Bioinformatics ,03 medical and health sciences ,0302 clinical medicine ,Steroidal hormones ,Receptors, Glucocorticoid ,medicine ,Medicine and Health Sciences ,Genetics ,Humans ,In patient ,MESSENGER-RNA EXPRESSION ,Side effects ,GSK3B ,Glucocorticoids ,DEXAMETHASONE-INDUCED APOPTOSIS ,ACUTE LYMPHOBLASTIC-LEUKEMIA ,business.industry ,MOLECULAR-MECHANISMS ,Lymphoproliferative Disorders ,Lymphoid malignancies ,Gene Expression Regulation, Neoplastic ,FACTOR-KAPPA-B ,RECEPTOR GENE ,030104 developmental biology ,MULTIPLE-MYELOMA CELLS ,Nuclear receptor ,Oncology ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,GLYCOGEN-SYNTHASE KINASE-3-BETA ,Quality of Life ,Glucocorticoid resistance ,INDUCED LEUCINE-ZIPPER ,Glucocorticoid Resistance ,business ,Glucocorticoid ,hormones, hormone substitutes, and hormone antagonists ,medicine.drug ,Signal Transduction - Abstract
Glucocorticoids are essential drugs in the treatment protocols of lymphoid malignancies. These steroidal hormones trigger apoptosis of the malignant cells by binding to the glucocorticoid receptor (GR), which is a member of the nuclear receptor superfamily. Long term glucocorticoid treatment is limited by two major problems: the development of glucocorticoid-related side effects, which hampers patient quality of life, and the emergence of glucocorticoid resistance, which is a gradual process that is inevitable in many patients. This emphasizes the need to reevaluate and optimize the widespread use of glucocorticoids in lymphoid malignancies. To achieve this goal, a deep understanding of the mechanisms governing glucocorticoid responsiveness is required, yet, a recent comprehensive overview is currently lacking. In this review, we examine how glucocorticoids mediate apoptosis by detailing GR's genomic and non-genomic action mechanisms in lymphoid malignancies. We continue with a discussion of the glucocorticoid-related problems and how these are intertwined with one another. We further zoom in on glucocorticoid resistance by critically analyzing the plethora of proposed mechanisms and highlighting therapeutic opportunities that emerge from these studies. In conclusion, early detection of glucocorticoid resistance in patients remains an important challenge as this would result in a timelier treatment reorientation and reduced glucocorticoid-instigated side effects.
- Published
- 2020
22. Combination therapy with charged particles and molecular targeting : a promising avenue to overcome radioresistance
- Author
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Katrien Konings, Charlot Vandevoorde, Bjorn Baselet, Sarah Baatout, and Marjan Moreels
- Subjects
0301 basic medicine ,Cancer Research ,carbon ion therapy ,medicine.medical_treatment ,PROTON-BEAM IRRADIATION ,Review ,RELATIVE BIOLOGICAL EFFECTIVENESS ,lcsh:RC254-282 ,Poly (ADP-Ribose) Polymerase Inhibitor ,POLY(ADP-RIBOSE) POLYMERASE INHIBITOR ,03 medical and health sciences ,0302 clinical medicine ,Cancer stem cell ,LINEAR-ENERGY-TRANSFER ,Radioresistance ,CANCER STEM-CELLS ,X-rays ,molecular targeted drugs ,medicine ,Medicine and Health Sciences ,proton therapy ,Proton therapy ,Science & Technology ,Particle therapy ,business.industry ,Cancer ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,medicine.disease ,PI3K/AKT/MTOR SIGNALING PATHWAY ,Radiation therapy ,radioresistance ,FACTOR-KAPPA-B ,030104 developmental biology ,Oncology ,particle therapy ,030220 oncology & carcinogenesis ,Cancer cell ,CARBON ION-BEAM ,Cancer research ,combination treatment ,DNA-REPAIR ,radiosensitization ,business ,GROWTH-FACTOR RECEPTOR ,Life Sciences & Biomedicine - Abstract
Radiotherapy plays a central role in the treatment of cancer patients. Over the past decades, remarkable technological progress has been made in the field of conventional radiotherapy. In addition, the use of charged particles (e.g., protons and carbon ions) makes it possible to further improve dose deposition to the tumor, while sparing the surrounding healthy tissues. Despite these improvements, radioresistance and tumor recurrence are still observed. Although the mechanisms underlying resistance to conventional radiotherapy are well-studied, scientific evidence on the impact of charged particle therapy on cancer cell radioresistance is restricted. The purpose of this review is to discuss the potential role that charged particles could play to overcome radioresistance. This review will focus on hypoxia, cancer stem cells, and specific signaling pathways of EGFR, NFκB, and Hedgehog as well as DNA damage signaling involving PARP, as mechanisms of radioresistance for which pharmacological targets have been identified. Finally, new lines of future research will be proposed, with a focus on novel molecular inhibitors that could be used in combination with charged particle therapy as a novel treatment option for radioresistant tumors. ispartof: FRONTIERS IN ONCOLOGY vol:10 ispartof: location:Switzerland status: published
- Published
- 2020
23. Human mesenchymal stromal cells broadly modulate high glucose-induced inflammatory responses of renal proximal tubular cell monolayers
- Author
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Stephanie Rocks, Joana Cabral, Tomás P. Griffin, Tara McMorrow, Jasmin McCaul, Elizabeth Sander, Nahidul Islam, Matthew D. Griffin, Junaid Qazi, Horizon 2020, Seventh Framework Programme, Science Foundation Ireland, Health Research Board, European Regional Development Fund, Hardiman Research Scholarship, National University of Ireland Galway, and Irish Endocrine Society/Royal College of Physicians of Ireland
- Subjects
0301 basic medicine ,Transcription, Genetic ,Cell ,030232 urology & nephrology ,Medicine (miscellaneous) ,Lipocalin ,ACTIVATION ,Kidney Tubules, Proximal ,0302 clinical medicine ,lcsh:QD415-436 ,Cells, Cultured ,Kidney ,lcsh:R5-920 ,Chemistry ,MONOCYTE CHEMOATTRACTANT PROTEIN-1 ,Interleukin ,EPITHELIAL-CELLS ,FACTOR-KAPPA-B ,medicine.anatomical_structure ,Molecular Medicine ,Stem cell ,Inflammation Mediators ,lcsh:Medicine (General) ,STEM-CELLS ,EXPRESSION ,Biochemistry, Genetics and Molecular Biology (miscellaneous) ,lcsh:Biochemistry ,03 medical and health sciences ,KIDNEY ,INJURY ,medicine ,Humans ,Secretion ,RNA, Messenger ,Cell Shape ,Inflammation ,THERAPEUTIC TARGET ,Research ,Macrophages ,Mesenchymal stem cell ,Epithelial Cells ,Mesenchymal Stem Cells ,Cell Biology ,INDUCED DIABETIC-NEPHROPATHY ,Molecular biology ,030104 developmental biology ,Glucose ,Gene Expression Regulation ,Culture Media, Conditioned ,Cytokine secretion ,Extracellular Space - Abstract
Background: Renal proximal tubular epithelial cells (RPTEC) are dysfunctional in diabetic kidney disease (DKD). Mesenchymal stromal cells (MSC) may modulate DKD pathogenesis through anti-inflammatory mediators. This study aimed to investigate the pro-inflammatory effect of extended exposure to high glucose (HG) concentration on stable RPTEC monolayers and the influence of MSC on this response.Methods: Morphologically stable human RPTEC/TERT1 cell monolayers were exposed to 5 mM and 30 mM (HG) D-glucose or to 5 mM D-glucose + 25 mM D-mannitol (MAN) for 5 days with sequential immunoassays of supernatants and end-point transcriptomic analysis by RNA sequencing. Under the same conditions, MSC-conditioned media (MSC-CM) or MSC-containing transwells were added for days 4-5. Effects of CM from HG- and MAN-exposed RPTEC/MSC co-cultures on cytokine secretion by monocyte-derived macrophages were determined.Results: After 72-80 h, HG resulted in increased RPTEC/TERT1 release of interleukin (IL)-6, IL-8, monocyte chemoattractant protein (MCP)-1 and neutrophil gelatinase-associated lipocalin (NGAL). The HG pro-inflammatory effect was attenuated by concentrated (10x) MSC-CM and, to a greater extent, by MSC transwell co-culture. Bioinformatics analysis of RNA sequencing data confirmed a predominant effect of HG on inflammation-related mediators and biological processes/KEGG pathways in RPTEC/TERT1 stable monolayers as well as the non-contact-dependent anti-inflammatory effect of MSC. Finally, CM from HG-exposed RPTEC/MSC transwell co-cultures was associated with attenuated secretion of inflammatory mediators by macrophages compared to CM from HG-stimulated RPTEC alone.Conclusions: Stable RPTEC monolayers demonstrate delayed pro-inflammatory response to HG that is attenuated by close proximity to human MSC. In DKD, this MSC effect has potential to modulate hyperglycemia-associated RPTEC/macrophage cross-talk. The research was supported by a grant from the European Commission [Horizon 2020 Collaborative Health Project NEPHSTROM (grant number 634086; TPG, MNI, MDG)]. Other funding sources that contributed to the work were grants from the European Commission [FP7 Collaborative Health Project VISICORT (grant number 602470; MDG, JC)], from Science Foundation Ireland [REMEDI Strategic Research Cluster (grant number 09/SRC-B1794; MDG) and CÚRAM Research Centre (grant number 13/RC/2073; MDG)], from the Health Research board of Ireland (grant number HRA_POR/2013/341; JC, MDG) and the European Regional Development Fund. TPG is supported by a Hardiman Scholarship from the College of Medicine, Nursing and Health Science, National University of Ireland Galway and a bursary from the Irish Endocrine Society/Royal College of Physicians of Ireland. JMcC and TMcM are funded by Science Foundation Ireland (grant number 12/IP/1686) and by the School of Biomolecular and Biomedical Science, University College Dublin. peer-reviewed
- Published
- 2019
24. Host–Microbial Interactions in Idiopathic Pulmonary Fibrosis
- Author
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Phillip James, Athol U. Wells, Saffron A.G. Willis-Owen, Michael J. Cox, Steven Cowman, Andrew D Blanchard, Carmel Stock, Cécile Daccord, Toby M. Maher, Michael R. Loebinger, William O.C.M. Cookson, Miriam F. Moffatt, Elisabetta A. Renzoni, Lindsay M. Edwards, Philip L. Molyneaux, British Lung Foundation, Wellcome Trust, National Institute for Health Research, and Medical Research Council (MRC)
- Subjects
Male ,0301 basic medicine ,Respiratory System ,PATHOGENESIS ,microbiome ,MUC5B PROMOTER POLYMORPHISM ,SUSCEPTIBILITY ,Critical Care and Intensive Care Medicine ,DISEASE ,Idiopathic pulmonary fibrosis ,0302 clinical medicine ,Usual interstitial pneumonia ,Medicine ,Prospective Studies ,usual interstitial pneumonia ,Respiratory system ,skin and connective tissue diseases ,PHOSPHORYLATION ,Prospective cohort study ,11 Medical and Health Sciences ,Whole blood ,medicine.diagnostic_test ,Microbiota ,ASSOCIATION ,respiratory system ,idiopathic pulmonary fibrosis ,NETWORKS ,FACTOR-KAPPA-B ,Real-time polymerase chain reaction ,Host-Pathogen Interactions ,Female ,Life Sciences & Biomedicine ,Bronchoalveolar Lavage Fluid ,Pulmonary and Respiratory Medicine ,03 medical and health sciences ,Critical Care Medicine ,General & Internal Medicine ,expression ,Humans ,Microbiome ,Aged ,Science & Technology ,business.industry ,Original Articles ,medicine.disease ,respiratory tract diseases ,030104 developmental biology ,Bronchoalveolar lavage ,acute lung injury ,030228 respiratory system ,EXACERBATION ,Immunology ,Microbial Interactions ,sense organs ,Transcriptome ,business ,LUNG INJURY ,Follow-Up Studies - Abstract
Changes in the respiratory microbiome are associated with disease progression in idiopathic pulmonary fibrosis (IPF). The role of the host response to the respiratory microbiome remains unknown.To explore the host-microbial interactions in IPF.Sixty patients diagnosed with IPF were prospectively enrolled together with 20 matched control subjects. Subjects underwent bronchoalveolar lavage (BAL), and peripheral whole blood was collected into PAXgene tubes for all subjects at baseline. For subjects with IPF, additional samples were taken at 1, 3, and 6 months and (if alive) 1 year. Gene expression profiles were generated using Affymetrix Human Gene 1.1 ST arrays.By network analysis of gene expression data, we identified two gene modules that strongly associated with a diagnosis of IPF, BAL bacterial burden (determined by 16S quantitative polymerase chain reaction), and specific microbial operational taxonomic units, as well as with lavage and peripheral blood neutrophilia. Genes within these modules that are involved in the host defense response include NLRC4, PGLYRP1, MMP9, and DEFA4. The modules also contain two genes encoding specific antimicrobial peptides (SLPI and CAMP). Many of these particular transcripts were associated with survival and showed longitudinal overexpression in subjects experiencing disease progression, further strengthening the relationship of the transcripts with disease.Integrated analysis of the host transcriptome and microbial signatures demonstrated an apparent host response to the presence of an altered or more abundant microbiome. These responses remained elevated in longitudinal follow-up, suggesting that the bacterial communities of the lower airways may act as persistent stimuli for repetitive alveolar injury in IPF.
- Published
- 2017
25. DTNI
- Author
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Diana M. Hendrickx, Jos C. S. Kleinjans, Terezinha Souza, Danyel Jennen, RS: GROW - R1 - Prevention, Promovendi ODB, and Toxicogenomics
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0301 basic medicine ,Time Factors ,Health, Toxicology and Mutagenesis ,Gene regulatory network ,Inference ,Gene Expression ,Toxicology ,Bioinformatics ,Toxicogenetics ,0302 clinical medicine ,ACETAMINOPHEN HEPATOTOXICITY ,Multiple time ,Gene Regulatory Networks ,INDUCED LIVER-INJURY ,General Medicine ,Toxicogenomics ,CANCER ,Dose-response ,FACTOR-KAPPA-B ,Mode of action ,030220 oncology & carcinogenesis ,Regression Analysis ,RISK-ASSESSMENT ,Chemical and Drug Induced Liver Injury ,Algorithms ,Signal Transduction ,Time series ,Drug-Related Side Effects and Adverse Reactions ,OUTCOME PATHWAYS ,Computational biology ,Biology ,Models, Biological ,Hazardous Substances ,DIFFERENTIAL EXPRESSION ,03 medical and health sciences ,Gene regulatory network inference ,Humans ,Computer Simulation ,KNOWLEDGE ,Key event ,Gene ,Dose-Response Relationship, Drug ,Ode ,Reproducibility of Results ,IN-VITRO ,Molecular initiating event ,030104 developmental biology ,GENE-EXPRESSION PROFILES ,Hepatocytes ,Dose–response - Abstract
Unravelling gene regulatory networks (GRNs) influenced by chemicals is a major challenge in systems toxicology. Because toxicant-induced GRNs evolve over time and dose, the analysis of global gene expression data measured at multiple time points and doses will provide insight in the adverse effects of compounds. Therefore, there is a need for mathematical methods for GRN identification from time-over-dose-dependent data. One of the current approaches for GRN inference is Time Series Network Identification (TSNI). TSNI is based on ordinary differential equations (ODE), describing the time evolution of the expression of each gene, which is assumed to be dependent on the expression of other genes and an external perturbation (i.e. chemical exposure). Here, we present Dose-Time Network Identification (DTNI), a method extending TSNI by including ODE describing how the expression of each gene evolves with dose, which is supposed to depend on the expression of other genes and the exposure time. We also adapted TSNI in order to enable inclusion of time-over-dose-dependent data from multiple compounds. Here, we show that DTNI outperforms TSNI in inferring a toxicant-induced GRN. Moreover, we show that DTNI is a suitable method to infer a GRN dose- and time-dependently induced by a group of compounds influencing a common biological process. Applying DTNI on experimental data from TG-GATEs, we demonstrate that DTNI provides in-depth information on the mode of action of compounds, in particular key events and potential molecular initiating events. Furthermore, DTNI also discloses several unknown interactions which have to be verified experimentally. Electronic supplementary material The online version of this article (doi:10.1007/s00204-016-1922-5) contains supplementary material, which is available to authorized users.
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- 2017
26. Small heterodimer partner (SHP) contributes to insulin resistance in cardiomyocytes
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Marta Tajes, Joost J. F. P. Luiken, Marie Miglianico, Emma Barroso, Ricardo Rodríguez-Calvo, Will A. Coumans, Dietbert Neumann, Jan F. C. Glatz, Manuel Vázquez-Carrera, Yvonne Oligschlaeger, Dipanjan Chanda, Moleculaire Genetica, RS: CARIM - R2.06 - Intermediate cardiac metabolism, RS: NUTRIM - R2 - Liver and digestive health, RS: NUTRIM - R2 - Gut-liver homeostasis, RS: NUTRIM - R1 - Metabolic Syndrome, Promovendi CD, Ondersteunend personeel CD, and RS: CARIM - R3.06 - The vulnerable plaque: makers and markers
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0301 basic medicine ,DOWN-REGULATION ,Glucose uptake ,CD36 ,Receptors, Cytoplasmic and Nuclear ,Diabetic cardiomyopathy ,Mice ,MOUSE MODELS ,Nuclear receptors ,Insulina ,Insulin ,Myocytes, Cardiac ,SOCS3 ,CARDIAC-HYPERTROPHY ,Diabetis ,NF-kappa B ,hemic and immune systems ,FACTOR-KAPPA-B ,MUSCLE-CELLS ,embryonic structures ,Small heterodimer partner ,Phosphorylation ,biological phenomena, cell phenomena, and immunity ,Signal Transduction ,ORPHAN NUCLEAR RECEPTOR ,medicine.medical_specialty ,animal structures ,chemical and pharmacologic phenomena ,HEART-DISEASE ,Biology ,FATTY-ACID TRANSPORT ,HEPATIC GLUCONEOGENESIS ,03 medical and health sciences ,Insulin resistance ,Downregulation and upregulation ,Internal medicine ,medicine ,Animals ,Humans ,RNA, Messenger ,Molecular Biology ,Protein kinase B ,Inflammation ,Myocardium ,Cell Biology ,medicine.disease ,Lipid Metabolism ,030104 developmental biology ,Endocrinology ,Glucose ,Gene Expression Regulation ,ACTIVATED RECEPTOR ,biology.protein - Abstract
Small heterodimer partner (SHP) is an atypical nuclear receptor expressed in heart that has been shown to inhibit the hypertrophic response. Here, we assessed the role of SHP in cardiac metabolism and inflammation. Mice fed a high-fat diet (HFD) displayed glucose intolerance accompanied by increased cardiac mRNA levels of Shp. In HL-1 cardiomyocytes, SHP overexpression inhibited both basal and insulin-stimulated glucose uptake and impaired the insulin signalling pathway (evidenced by reduced AKT and AS160 phosphorylation), similar to insulin resistant cells generated by high palmitate/high insulin treatment (HP/HI; 500μM/100nM). In addition, SHP overexpression increased Socs3 mRNA and reduced IRS-1 protein levels. SHP overexpression also induced Cd36 expression (~6.2 fold; p
- Published
- 2017
27. The angiotensin type 2 receptor and the kidney
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RENAL-FUNCTION ,BLOOD-PRESSURE ,AT(2) RECEPTOR ,angiotensin ,renal physiology ,II RECEPTORS ,OBESE ZUCKER RATS ,DIABETIC-NEPHROPATHY ,FACTOR-KAPPA-B ,AT2-receptor ,AT2 RECEPTOR ,nephropathy ,COMPOUND 21 ,SPONTANEOUSLY HYPERTENSIVE-RATS - Abstract
Purpose of reviewAngiotensin II is a main regulator of kidney function. Renal actions mediated by the angiotensin AT(1) receptor have been well known for many years. In contrast, several details of angiotensin AT(2) receptor actions in kidney physiology and pathophysiology were only described very recently. These findings are reviewed in this article.Recent findingsRegarding the role of the angiotensin AT(2) receptor in kidney physiology, a major recent finding was that the AT(2) receptor-mediated inhibition of Na+-H+ exchanger-3 and Na+/K+-ATPase in the renal proximal tubules is caused by internalisation of these transporters, thus reducing reabsorption and increasing natriuresis/diuresis. Regarding renal pathology, several studies demonstrated an attenuation of renal injury caused by diabetes or by obesity with or without high-salt diet through anti-inflammatory, antifibrotic, and antioxidative mechanisms. Generally, AT(2) receptor expression seems increased and AT(2) receptor-mediated effects stronger in female and obese animals.SummaryThe recent findings about the role of the angiotensin AT(2) receptor in renal health and disease strongly suggest that pharmacological targeting of this receptor with selective agonists is a promising therapeutic strategy for inducing diuresis/natriuresis (also additive to established diuretics) and for the treatment of diabetic nephropathy or kidney disease of other pathogenesis.
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- 2017
28. Tumor growth suppression using a combination of taxol-based therapy and GSK3 inhibition in non-small cell lung cancer
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Linda O'Flaherty, Steven D Shnyder, Patricia A Cooper, Stephen J Cross, James G Wakefield, Olivier E Pardo, Michael J Seckl, and Jeremy M Tavaré
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Science & Technology ,General Science & Technology ,Science ,GLYCOGEN-SYNTHASE KINASE-3 ,PACLITAXEL ,Multidisciplinary Sciences ,FACTOR-KAPPA-B ,TARGET ,MD Multidisciplinary ,SURVIVAL ,Medicine ,Science & Technology - Other Topics - Abstract
Glycogen synthase kinase-3 (GSK3) is over-expressed and hyperactivated in non-small cell lung carcinoma (NSCLC) and plays a role in ensuring the correct alignment of chromosomes on the metaphase plate during mitosis through regulation of microtubule stability. This makes the enzyme an attractive target for cancer therapy. We examined the effects of a selective cell-permeant GSK3 inhibitor (CHIR99021), used alone or in combination with paclitaxel, using an in vitro cell growth assay, a quantitative chromosome alignment assay, and a tumor xenograft model. CHIR99021 inhibits the growth of human H1975 and H1299 NSCLC cell lines in a synergistic manner with paclitaxel. CHIR99021 and paclitaxel promoted a synergistic defect in chromosomal alignment when compared to each compound administered as monotherapy. Furthermore, we corroborated our in vitro findings in a mouse tumor xenograft model. Our results demonstrate that a GSK3 inhibitor and paclitaxel act synergistically to inhibit the growth of NSCLC cells in vitro and in vivo via a mechanism that may involve converging modes of action on microtubule spindle stability and thus chromosomal alignment during metaphase. Our findings provide novel support for the use of the GSK3 inhibitor, CHIR99021, alongside taxol-based chemotherapy in the treatment of human lung cancer.
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- 2019
29. Receptor activator of nuclear factor kB ligand, osteoprotegerin, and risk of death following a breast cancer diagnosis: results from the EPIC cohort
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Helena Schock, Kay Tee Kaw, Elisabete Weiderpass, José María Huerta, Eva Ardanaz, Rudolf Kaaks, Carlotta Sacerdote, Petra H.M. Peeters, Dagfinn Aune, Carla H. van Gils, Claudia Agnoli, Heiner Boeing, Anna Karakatsani, Anja Olsen, Antonia Trichopoulou, Mathilde His, Theron Johnson, Renée T. Fortner, Kim Overvad, Antonio Agudo, Anne Tjønneland, Marina Kvaskoff, Elio Riboli, Laure Dossus, Giovanna Masala, Agnès Fournier, Miguel Rodríguez-Barranco, Leire Gil, Carlo La Vecchia, Salvatore Panico, Danja Sarink, Jenny Chang-Claude, Patrick Arveux, Julie A. Schmidt, Rosario Tumino, Fortner, Renée T [0000-0002-1426-8505], Apollo - University of Cambridge Repository, Sarink, Danja, Schock, Helena, Johnson, Theron, Chang-Claude, Jenny, Overvad, Kim, Olsen, Anja, Tjønneland, Anne, Arveux, Patrick, Fournier, Agnè, Kvaskoff, Marina, Boeing, Heiner, Karakatsani, Anna, Trichopoulou, Antonia, La Vecchia, Carlo, Masala, Giovanna, Agnoli, Claudia, Panico, Salvatore, Tumino, Rosario, Sacerdote, Carlotta, van Gils, Carla H, Peeters, Petra H M, Weiderpass, Elisabete, Agudo, Antonio, Rodríguez-Barranco, Miguel, Huerta, José María, Ardanaz, Eva, Gil, Leire, Kaw, Kay Tee, Schmidt, Julie A, Dossus, Laure, His, Mathilde, Aune, Dagfinn, Riboli, Elio, Kaaks, Rudolf, and Fortner, Renée T
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0301 basic medicine ,Oncology ,Cancer Research ,Epidemiology ,PROLACTIN ,Cohort Studies ,0302 clinical medicine ,Breast cancer ,Surgical oncology ,Limit of Detection ,Reproductive ,serum biomarkers of endogenous exposures ,biology ,Hazard ratio ,RANKL ,Middle Aged ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Prognosis ,BONE METASTASIS ,3. Good health ,European Prospective Investigation into Cancer and Nutrition ,FACTOR-KAPPA-B ,reproductive, hormonal, and related factors ,POSTMENOPAUSAL WOMEN ,030220 oncology & carcinogenesis ,Cohort ,GROWTH ,Female ,and related factors ,Life Sciences & Biomedicine ,Serum biomarkers of endogenous exposures ,Research Article ,EXPRESSION ,musculoskeletal diseases ,Adult ,Risk ,medicine.medical_specialty ,Breast Neoplasms ,lcsh:RC254-282 ,Càncer de mama ,03 medical and health sciences ,Osteoprotegerin ,POOR-PROGNOSIS ,Internal medicine ,Genetics ,medicine ,Humans ,Oncology & Carcinogenesis ,Epidemiologia ,Aged ,Science & Technology ,business.industry ,VDP::Medical disciplines: 700::Clinical medical disciplines: 750::Oncology: 762 ,RANK Ligand ,medicine.disease ,hormonal ,VDP::Medisinske Fag: 700::Klinisk medisinske fag: 750::Onkologi: 762 ,030104 developmental biology ,ESTROGEN-RECEPTOR ,Reproductive, hormonal, and related factor ,Case-Control Studies ,biology.protein ,OPG ,business ,Reproductive, hormonal, and related factors ,1112 Oncology And Carcinogenesis - Abstract
Published version, available at: https://doi.org/10.1186/s12885-018-4887-3 Background Receptor activator of nuclear factor kappa-B (RANK)-signaling is involved in tumor growth and spread in experimental models. Binding of RANK ligand (RANKL) to RANK activates signaling, which is inhibited by osteoprotegerin (OPG). We have previously shown that circulating soluble RANKL (sRANKL) and OPG are associated with breast cancer risk. Here we extend these findings to provide the first data on pre-diagnosis concentrations of sRANKL and OPG and risk of breast cancer-specific and overall mortality after a breast cancer diagnosis. Methods Two thousand six pre- and postmenopausal women with incident invasive breast cancer (1620 (81%) with ER+ disease) participating in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort were followed-up for mortality. Pre-diagnosis concentrations of sRANKL and OPG were quantified in baseline serum samples using an enzyme-linked immunosorbent assay and electrochemiluminescent assay, respectively. Hazard ratios (HRs) and 95% confidence intervals (CIs) for breast cancer-specific and overall mortality were calculated using Cox proportional hazards regression models. Results Especially in women with ER+ disease, higher circulating OPG concentrations were associated with higher risk of breast cancer-specific (quintile 5 vs 1 HR 1.77 [CI 1.03, 3.04]; ptrend 0.10) and overall mortality (q5 vs 1 HR 1.39 [CI 0.94, 2.05]; ptrend 0.02). sRANKL and the sRANKL/OPG ratio were not associated with mortality following a breast cancer diagnosis. Conclusions High pre-diagnosis endogenous concentrations of OPG, the decoy receptor for RANKL, were associated with increased risk of death after a breast cancer diagnosis, especially in those with ER+ disease. These results need to be confirmed in well-characterized patient cohorts.
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- 2018
30. Resveratrol improves TNF-α-induced endothelial dysfunction in a coculture model of a Caco-2 with an endothelial cell line
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Katleen Raes, Senem Kamiloglu, Marilde T. Bordignon-Luiz, Guy Smagghe, Charlotte Grootaert, John Van Camp, Isabela Maia Toaldo, Esra Capanoglu, and Gerard Bryan Gonzales
- Subjects
0301 basic medicine ,BIOAVAILABILITY ,Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,Clinical Biochemistry ,Cell Communication ,METABOLITES ,Biochemistry ,Antioxidants ,Intestinal absorption ,chemistry.chemical_compound ,Stilbenes ,ABSORPTION ,OXIDATIVE STRESS ,Endothelial dysfunction ,NEOVASCULARIZATION ,ICAM-1 ,Nutrition and Dietetics ,Sulfates ,Vascular Endothelial Growth Factors ,Anti-Inflammatory Agents, Non-Steroidal ,Intercellular Adhesion Molecule-1 ,Cardiovascular disease ,CANCER ,Intestine ,Cell biology ,Vascular endothelial growth factor ,Endothelial stem cell ,FACTOR-KAPPA-B ,Inflammation Mediators ,EXPRESSION ,GROWTH-FACTOR ,medicine.medical_specialty ,Biology ,Nitric Oxide ,Cell Line ,Proinflammatory cytokine ,03 medical and health sciences ,Glucuronides ,Internal medicine ,medicine ,Humans ,Interleukin 8 ,NITRIC-OXIDE SYNTHASE ,Molecular Biology ,030109 nutrition & dietetics ,Tumor Necrosis Factor-alpha ,Growth factor ,Interleukin-8 ,Biology and Life Sciences ,Nitric oxide ,medicine.disease ,Coculture Techniques ,Coculture ,Oxidative Stress ,Enterocytes ,030104 developmental biology ,Endocrinology ,Intestinal Absorption ,chemistry ,Resveratrol ,Endothelium, Vascular ,Caco-2 Cells ,Reactive Oxygen Species ,Biomarkers - Abstract
The bioactivity of trans-resveratrol (RSV), an important wine polyphenol, and of its metabolites was investigated in a more relevant setup comprising an in vitro coculture cell model that combines intestinal absorption and conjugation with changes in endothelial function, which is primarily affected in cardiovascular diseases. Caco-2 and endothelial EA.hy926 cells were grown in a coculture, and Caco-2 cells were treated with RSV in the coculture and in two different sequential setups for 4 h and 24 h. Transported metabolites were investigated by UPLC-MS/MSE, and the effects on NO production, ROS inhibition and secretion of vascular endothelial growth factor (VEGF), interleukin-8 (IL-8) and intercellular adhesion molecule-1 (ICAM-1) were evaluated in TNF-α-activated and nonactivated endothelial cells. RSV and four conjugated metabolites, two sulfates and two glucuronides, were identified after intestinal transport. In both coculture and sequential systems, RSV at 20 μM strongly induced NO production. Changes in ROS and NO levels demonstrated a clear effect of crosstalk between cells in the coculture. The secretion of proinflammatory cytokines and VEGF was largely increased by treatment with TNF-α (inflammatory condition). The polyphenol intervention significantly reduced the levels of VEGF, ROS, IL-8 and ICAM-1, with a more pronounced effect in TNF-α-activated endothelial cells. In conclusion, RSV and its metabolites showed accentuated bioactivity on TNF-α-induced inflammation, and the metabolism of endothelial cells as a biological target was not only influenced by these phenolics but also by the communication between distinct cell lines, showing a new perspective for investigations on polyphenol intervention and its biological outcomes.
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- 2016
31. Cyclic AMP Effectors Regulate Myometrial Oxytocin Receptor Expression
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Mark R. Johnson, Angela Yulia, Suren R. Sooranna, Kaiyu Lei, Natasha Singh, and Action Medical Research
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0301 basic medicine ,Small interfering RNA ,SMOOTH-MUSCLE-CELLS ,Interleukin-1beta ,Gene Expression ,PREGNANT HUMAN MYOMETRIUM ,MESSENGER-RIBONUCLEIC-ACID ,chemistry.chemical_compound ,Endocrinology ,Pregnancy ,Gene expression ,Cyclic AMP ,Guanine Nucleotide Exchange Factors ,RNA, Small Interfering ,Receptor ,Cells, Cultured ,Labor, Obstetric ,G-ALPHA-S ,Myometrium ,11 Medical And Health Sciences ,FACTOR-KAPPA-B ,Receptors, Oxytocin ,Female ,Life Sciences & Biomedicine ,Adenosine monophosphate ,medicine.medical_specialty ,ADENOSINE-MONOPHOSPHATE ,In Vitro Techniques ,Biology ,DIFFERENTIAL EXPRESSION ,Endocrinology & Metabolism ,03 medical and health sciences ,PHOSPHODIESTERASE ACTIVITY ,Internal medicine ,medicine ,Humans ,Protein kinase A ,PROTEIN-KINASE-A ,PROGESTERONE-RECEPTOR ,Messenger RNA ,Science & Technology ,Colforsin ,06 Biological Sciences ,Cyclic AMP-Dependent Protein Kinases ,Oxytocin receptor ,030104 developmental biology ,chemistry ,07 Agricultural And Veterinary Sciences - Abstract
The factors that initiate human labor are poorly understood. We have tested the hypothesis that a decline in cAMP/protein kinase A (PKA) function leads to the onset of labor. Initially, we identified myometrial cAMP/PKA-responsive genes (six up-regulated and five down-regulated genes) and assessed their expression in myometrial samples taken from different stages of pregnancy and labor. We found that the oxytocin receptor (OTR) was one of the cAMP-repressed genes, and, given the importance of OTR in the labor process, we studied the mechanisms involved in greater detail using small interfering RNA, chemical agonists, and antagonists of the cAMP effectors. We found that cAMP-repressed genes, including OTR, increased with the onset of labor. Our in vitro studies showed that cAMP acting via PKA reduced OTR expression but that in the absence of PKA, cAMP acts via exchange protein activated by cAMP (EPAC) to increase OTR expression. In early labor myometrial samples, PKA levels and activity declined and Epac1 levels increased, perhaps accounting for the increase in myometrial OTR mRNA and protein levels at this time. In vitro exposure of myometrial cells to stretch and IL-1β increased OTR levels and reduced basal and forskolin-stimulated cAMP and PKA activity, as judged by phospho-cAMP response element-binding protein levels, but neither stretch nor IL-1β had any effect on PKA or EPAC1 levels. In summary, there is a reduction in the activity of the cAMP/PKA pathway with the onset of human labor potentially playing a critical role in regulating OTR expression and the transition from myometrial quiescence to activation.
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- 2016
32. Induction of Osmolyte Pathways in Skeletal Muscle Inflammation: Novel Biomarkers for Myositis
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Jana Zschüntzsch, Tea Šokčević, Jens Schmidt, Boel De Paepe, Joachim Weis, and Jan De Bleecker
- Subjects
EXPRESSION ,0301 basic medicine ,MYOPATHIES ,inflammatory myopathy ,PROTEIN ,Inflammation ,inflammatory stress ,Polymyositis ,lcsh:RC346-429 ,DUCHENNE MUSCULAR-DYSTROPHY ,ACTIVATION ,Inflammatory myopathy ,TAURINE ,03 medical and health sciences ,0302 clinical medicine ,INCLUSION-BODY MYOSITIS ,Medicine and Health Sciences ,medicine ,Gene silencing ,Myocyte ,TRANSCRIPTION FACTOR ,ddc:610 ,lcsh:Neurology. Diseases of the nervous system ,Original Research ,muscle regeneration ,osmolytes ,Myogenesis ,Chemistry ,Biology and Life Sciences ,Skeletal muscle ,medicine.disease ,3. Good health ,Cell biology ,FACTOR-KAPPA-B ,DIFFERENTIATION ,030104 developmental biology ,medicine.anatomical_structure ,Neurology ,osmotic stress ,Neurology (clinical) ,medicine.symptom ,Inclusion body myositis ,030217 neurology & neurosurgery - Abstract
We recently identified osmolyte accumulators as novel biomarkers for chronic skeletal muscle inflammation and weakness, but their precise involvement in inflammatory myopathies remains elusive. In the current study, we demonstrate in vitro that, in myoblasts and myotubes exposed to pro-inflammatory cytokines or increased salt concentration, mRNA levels of the osmolyte carriers SLC5A3, SLC6A6, SLC6A12, and AKR1B1 enzyme can be upregulated. Induction of SLC6A12 and AKR1B1 was confirmed at the protein level using immunofluorescence and Western blotting. Gene silencing by specific siRNAs revealed that these factors were vital for muscle cells under hyperosmotic conditions. Pro-inflammatory cytokines activated mitogen-activated protein kinases, nuclear factor kappa B as well as nuclear factor of activated T-cells 5 mRNA expression. In muscle biopsies from patients with polymyositis or sporadic inclusion body myositis, osmolyte pathway activation was observed in regenerating muscle fibers. In addition, the osmolyte carriers SLC5A3 and SLC6A12 localized to subsets of immune cells, most notably to the endomysial macrophages and T-cells. Collectively, this study unveiled that muscle cells respond to osmotic and inflammatory stress by osmolyte pathway activation, likely orchestrating general protection of the tissue. Moreover, pro-inflammatory properties are attributed to SLC5A3 and SLC6A12 in auto-aggressive macrophages and T-cells in inflamed skeletal muscle.
- Published
- 2018
33. Dimethyl fumarate induces a persistent change in the composition of the innate and adaptive immune system in multiple sclerosis patients
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Judith Fraussen, B. Van Wijmeersch, G. Montes Diaz, Raymond Hupperts, Veerle Somers, RS: MHeNs - R1 - Cognitive Neuropsychiatry and Clinical Neuroscience, Klinische Neurowetenschappen, and MUMC+: MA Med Staf Spec Neurologie (9)
- Subjects
Male ,Dimethyl Fumarate ,T-Lymphocytes ,lcsh:Medicine ,NUCLEAR-FACTOR ,Adaptive Immunity ,chemistry.chemical_compound ,NATURAL-KILLER-CELLS ,0302 clinical medicine ,Interferon ,MEMORY T-CELLS ,ORAL BG-12 ,Macrophage ,lcsh:Science ,B-Lymphocytes ,Multidisciplinary ,biology ,Dimethyl fumarate ,medicine.diagnostic_test ,Chemistry ,Middle Aged ,Acquired immune system ,FACTOR-KAPPA-B ,Female ,Immunosuppressive Agents ,medicine.drug ,Adult ,EXPRESSION ,Multiple Sclerosis ,Antigen presentation ,AUTOIMMUNE ,Article ,Flow cytometry ,03 medical and health sciences ,Young Adult ,Immune system ,medicine ,Humans ,PLACEBO-CONTROLLED PHASE-3 ,CD40 ,lcsh:R ,ACID ESTERS ,Molecular biology ,Immunity, Innate ,Cross-Sectional Studies ,biology.protein ,lcsh:Q ,030217 neurology & neurosurgery ,030215 immunology ,Follow-Up Studies ,RESPONSES - Abstract
The effects of dimethyl fumarate (DMF) on the immune system in multiple sclerosis (MS) are not completely elucidated. In this study, an extensive immunophenotypic analysis of innate and adaptive immune cells of DMF-treated MS patients was performed. Peripheral blood immune cell phenotypes were determined using flow cytometry in a follow-up study of 12 MS patients before, after 3 and 12 months of DMF treatment and a cross-sectional study of 25 untreated and 64 DMF-treated MS patients. Direct effects of DMF on B cells were analyzed in vitro. After 12 months of DMF treatment, percentages of monocytes, natural killer cells, naive T and B cells and transitional B cells increased. Percentages of (effector) memory T cells, (non) class-switched memory B cells and double negative B cells decreased together with CD4(+) T cells expressing interferon-gamma (IFN-gamma), granulocyte macrophage colony-stimulating factor (GM-CSF) and interleukin-17 (IL-17). DMF treatment was fully effective as of 6 months and directly induced apoptosis and decreased expression of costimulatory CD40, antigen presentation molecule MHCII and B cell activating factor receptor (BAFFR) on B cells. DMF induced a persistent change of the immune system of MS patients, directly induced apoptosis and reduced expression of functional markers on B cells. We thank Igna Rutten and Kim Ulenaers (Hasselt University, Biomedical Research Institute and UBilim), Rehabilitation & MS Center (Overpelt), Sandra Liedekerken, Tiny Kempkens, Judith Poeth, Lianne van Gennip and all MS nurses at Zuyderland Medisch Centrum (Sittard) for patient recruitment and sample collection. We thank prof. dr. Niels Hellings for critical reading. This work was supported by Hasselt University and Maastricht University. Funding was provided via an investigator-initiated trial grant from Biogen. J. Fraussen is a postdoctoral fellow of the Fund for Scientific Research, Flanders.
- Published
- 2018
34. HX600, a synthetic agonist for RXR-Nurr1 heterodimer complex, prevents ischemia-induced neuronal damage
- Author
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Natalia Kolosowska, Hiramani Dhungana, Jari Koistinaho, Gary E. Landreth, Alexandra Grubman, Anthony R. White, H. Kagechika, Yuriy Pomeshchik, M. Giordano, Olli Kärkkäinen, Sanna Loppi, Sara Wojciechowski, Mikko T. Huuskonen, Paula Korhonen, Kati Hanhineva, Katja M. Kanninen, Seppo Auriola, Tarja Malm, Neuroscience Center, and University of Helsinki
- Subjects
0301 basic medicine ,RESONANCE-SPECTROSCOPY ,ORPHAN NUCLEAR RECEPTORS ,Cerebral arteries ,Receptors, Cytoplasmic and Nuclear ,Pharmacology ,Brain Ischemia ,Brain ischemia ,Behavioral Neuroscience ,Mice ,0302 clinical medicine ,Neuroinflammation ,Nuclear receptors ,Dibenzazepines ,Nuclear Receptor Subfamily 4, Group A, Member 2 ,Metabolic profiling ,OXIDATIVE STRESS ,Receptors, Immunologic ,Neurons ,Membrane Glycoproteins ,Microglia ,MOLECULAR-MECHANISMS ,Brain ,MOUSE STROKE MODEL ,Infarction, Middle Cerebral Artery ,3. Good health ,Stroke ,FACTOR-KAPPA-B ,medicine.anatomical_structure ,Neuroprotective Agents ,medicine.symptom ,Agonist ,medicine.drug_class ,Immunology ,Primary Cell Culture ,Ischemia ,Inflammation ,Article ,Proinflammatory cytokine ,03 medical and health sciences ,MIDDLE CEREBRAL-ARTERY ,medicine ,Animals ,NITRIC-OXIDE SYNTHASE ,IMMEDIATE-EARLY GENES ,Endocrine and Autonomic Systems ,business.industry ,3112 Neurosciences ,medicine.disease ,PHOSPHOLIPASE A(2) ,Mice, Inbred C57BL ,Disease Models, Animal ,030104 developmental biology ,Retinoid X Receptors ,Nerve Degeneration ,business ,030217 neurology & neurosurgery - Abstract
Ischemic stroke is amongst the leading causes of death and disabilities. The available treatments are suitable for only a fraction of patients and thus novel therapies are urgently needed. Blockage of one of the cerebral arteries leads to massive and persisting inflammatory reaction contributing to the nearby neuronal damage. Targeting the detrimental pathways of neuroinflammation has been suggested to be beneficial in conditions of ischemic stroke. Nuclear receptor 4A-family (NR4A) member Nurr1 has been shown to be a potent modulator of harmful inflammatory reactions, yet the role of Nurr1 in cerebral stroke remains unknown. Here we show for the first time that an agonist for the dimeric transcription factor Nurr1/retinoid X receptor (RXR), HX600, reduces microglia expressed proinflammatory mediators and prevents inflammation induced neuronal death in in vitro co-culture model of neurons and microglia. Importantly, HX600 was protective in a mouse model of permanent middle cerebral artery occlusion and alleviated the stroke induced motor deficits. Along with the anti-inflammatory capacity of HX600 in vitro, treatment of ischemic mice with HX600 reduced ischemia induced Iba-1, p38 and TREM2 immunoreactivities, protected endogenous microglia from ischemia induced death and prevented leukocyte infiltration. These anti-inflammatory functions were associated with reduced levels of brain lysophosphatidylcholines (lysoPCs) and acylcarnitines, metabolites related to proinflammatory events. These data demonstrate that HX600 driven Nurr1 activation is beneficial in ischemic stroke and propose that targeting Nurr1 is a novel candidate for conditions involving neuroinflammatory component.
- Published
- 2018
35. Interplay between hypercholesterolaemia and inflammation in atherosclerosis: Translating experimental targets into clinical practice
- Author
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Tuñón, José, Bäck, Magnus, Badimón, Lina, Bochaton-Piallat, Marie-Luce, Cariou, Bertrand, Daemen, Mat J., Egido, Jesus, Evans, Paul C., Francis, Sheila E., Ketelhuth, Daniel Fj, Lutgens, Esther, Matter, Christian M., Monaco, Claudia, Steffens, Sabine, Stroes, Erik, Vindis, Cécile, Weber, Christian, Hoefer, Imo E., Atherosclerosis, ESC Working Group, Biology, Vascular, Department of Cardiology, Karolinska University Hospital, Karolinska Institutet [Stockholm], Department of Medicine [Karolinska Institute], Karolinska University Hospital [Stockholm], Consejo Superior de Investigaciones Científicas [Madrid] (CSIC), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), ACS - Atherosclerosis & ischemic syndromes, Pathology, Medical Biochemistry, AII - Inflammatory diseases, Vascular Medicine, ACS - Heart failure & arrhythmias, Biochemie, and RS: CARIM - R3.07 - Structure-function analysis of the chemokine interactome for therapeutic targeting and imaging in atherosclerosis
- Subjects
0301 basic medicine ,STATIN THERAPY ,Epidemiology ,interleukin-1β ,[SDV]Life Sciences [q-bio] ,Anti-Inflammatory Agents ,ddc:616.07 ,030204 cardiovascular system & hematology ,Bioinformatics ,immune response ,law.invention ,Coronary artery disease ,0302 clinical medicine ,Randomized controlled trial ,Risk Factors ,law ,Clinical Trials as Topic ,Evidence-Based Medicine ,biology ,Antibodies, Monoclonal ,RANDOMIZED CONTROLLED-TRIAL ,Lipids ,C-REACTIVE PROTEIN ,3. Good health ,Lipoproteins, LDL ,FACTOR-KAPPA-B ,Treatment Outcome ,NATIONWIDE COHORT ,Rheumatoid arthritis ,CORONARY-ARTERY-DISEASE ,Inflammation Mediators ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,medicine.drug ,Hypercholesterolemia ,Inflammation ,Antibodies, Monoclonal, Humanized ,canakinumab ,03 medical and health sciences ,medicine ,Humans ,CARDIOVASCULAR EVENTS ,business.industry ,C-reactive protein ,medicine.disease ,SECONDARY ANALYSIS ,RHEUMATOID-ARTHRITIS ,Blockade ,Clinical trial ,Canakinumab ,030104 developmental biology ,inflammation ,biology.protein ,MONOCLONAL-ANTIBODIES ,atherosclerosis ,business ,Biomarkers ,interleukin-1 - Abstract
International audience; Dyslipidaemia and inflammation are closely interconnected in their contribution to atherosclerosis. In fact, low-density lipoprotein (LDL)-lowering drugs have anti-inflammatory effects. The Canakinumab Antiinflammatory Thrombosis Outcome Study (CANTOS) has shown that interleukin (IL)-1β blockade reduces the incidence of cardiovascular events in patients with previous myocardial infarction and C-reactive protein levels \textgreater2 mg/L. These data confirm the connection between lipids and inflammation, as lipids activate the Nod-like receptor protein 3 inflammasome that leads to IL-1β activation. LDL-lowering drugs are the foundation of cardiovascular prevention. Now, the CANTOS trial demonstrates that combining them with IL-1β blockade further decreases the incidence of cardiovascular events. However, both therapies are not at the same level, given the large evidence showing that LDL-lowering drugs reduce cardiovascular risk as opposed to only one randomized trial of IL-1β blockade. In addition, IL-1β blockade has only been studied in patients with C-reactive protein \textgreater2 mg/L, while the benefit of LDL-lowering is not restricted to these patients. Also, lipid-lowering drugs are not harmful even at very low ranges of LDL, while anti-inflammatory therapies may confer a higher risk of developing fatal infections and sepsis. In the future, more clinical trials are needed to explore whether targeting other inflammatory molecules, both related and unrelated to the IL-1β pathway, reduces the cardiovascular risk. In this regard, the ongoing trials with methotrexate and colchicine may clarify whether the cardiovascular benefit of IL-1β blockade extends to other anti-inflammatory mechanisms. A positive result would represent a major change in the future treatment of atherosclerosis.
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- 2018
36. Progesterone, the maternal immune system and the onset of parturition in the mouse
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Bronwen R. Herbert, Simon N. Waddington, Danijela Markovic, David A. MacIntyre, Mark R. Johnson, Lydia F Edey, Renyi Hua, Kieran P. O'Dea, Sam Mesiano, Philip R. Bennett, Kaiyu Lei, Masao Takata, and Hector Georgiou
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0301 basic medicine ,Chemokine ,Neutrophils ,medicine.medical_treatment ,Monocytes ,Mice ,0302 clinical medicine ,FETAL MEMBRANES ,IN-VIVO ,INDUCED PRETERM LABOR ,GENE-EXPRESSION ,Reproductive Biology ,030219 obstetrics & reproductive medicine ,biology ,myometrium ,Myometrium ,MONOCYTE CHEMOATTRACTANT PROTEIN-1 ,General Medicine ,11 Medical And Health Sciences ,Mifepristone ,FACTOR-KAPPA-B ,medicine.anatomical_structure ,Cytokine ,Female ,Chemokines ,medicine.symptom ,Life Sciences & Biomedicine ,leukocytes ,MYOMETRIAL INFLAMMATION ,Inflammation ,progesterone ,TERM ,Andrology ,LY-6C(HIGH) MONOCYTES ,03 medical and health sciences ,Immune system ,medicine ,Animals ,Obstetrics & Reproductive Medicine ,Innate immune system ,Science & Technology ,Monocyte ,Parturition ,Cell Biology ,CYTOKINE PRODUCTION ,06 Biological Sciences ,cytokines ,030104 developmental biology ,Reproductive Medicine ,Cyclooxygenase 2 ,inflammation ,Connexin 43 ,biology.protein ,Cyclooxygenase - Abstract
The role of progesterone (P4) in the regulation of the local (uterine) and systemic innate immune system, myometrial expression of connexin 43 (Cx-43) and cyclooxygenase 2 (COX-2), and the onset of parturition was examined in (i) naïve mice delivering at term; (ii) E16 mice treated with RU486 (P4-antagonist) to induce preterm parturition; and (iii) in mice treated with P4 to prevent term parturition. In naïve mice, myometrial neutrophil and monocyte numbers peaked at E18 and declined with the onset of parturition. In contrast, circulating monocytes did not change and although neutrophils were increased with pregnancy, they did not change across gestation. The myometrial mRNA and protein levels of most chemokines/cytokines, Cx-43, and COX-2 increased with, but not before, parturition. With RU486-induced parturition, myometrial and systemic neutrophil numbers increased before and myometrial monocyte numbers increased with parturition only. Myometrial chemokine/cytokine mRNA abundance increased with parturition, but protein levels peaked earlier at between 4.5 and 9 h post-RU486. Cx-43, but not COX-2, mRNA expression and protein levels increased prior to the onset of parturition. In mice treated with P4, the gestation-linked increase in myometrial monocyte, but not neutrophil, numbers was prevented, and expression of Cx-43 and COX-2 was reduced. On E20 of P4 supplementation, myometrial chemokine/cytokine and leukocyte numbers, but not Cx-43 and COX-2 expression, increased. These data show that during pregnancy P4 controls myometrial monocyte infiltration, cytokine and prolabor factor synthesis via mRNA-dependent and independent mechanisms and, with prolonged P4 supplementation, P4 action is repressed resulting in increased myometrial inflammation.
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- 2017
37. Selective Glucocorticoid Receptor Properties of GSK866 Analogs with Cysteine Reactive Warheads
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Xaveer Van Ostade, Kris Gevaert, Balu Kamaraj, Wim Vanden Berghe, Karolien De Bosscher, Ajay Palagani, Winnok H. De Vos, Bart Ruttens, Nadia Bougarne, Hans De Winter, Ken Declerck, Pieter Van der Veken, Marinus W C Verbeek, Ryabtsova Oksana, Koen Augustyns, Annemie Bogaerts, Jurgen Joossens, René Houtman, and Chandra Sekhar Chirumamilla
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0301 basic medicine ,Drug ,TOPICAL TREATMENT ,lcsh:Immunologic diseases. Allergy ,IMPROVED THERAPEUTIC INDEX ,DEXAMETHASONE 21-MESYLATE ,media_common.quotation_subject ,Immunology ,Pharmacology ,NFkB ,law.invention ,03 medical and health sciences ,Transactivation ,Glucocorticoid receptor ,TISSUE-CULTURE CELLS ,law ,glucocorticoid receptor ,Immunology and Allergy ,NF kappa B ,CRYSTAL-STRUCTURE ,SEGRA ,Biology ,cysteine ,media_common ,TUMOR-NECROSIS-FACTOR ,Original Research ,Reporter gene ,Chemistry ,INFLAMMATORY SKIN DISEASES ,MOLECULAR-MECHANISMS ,Pharmacology. Therapy ,Biology and Life Sciences ,COVALENT INHIBITORS ,NFKB1 ,covalent warhead ,electrophilic ,FACTOR-KAPPA-B ,030104 developmental biology ,Biochemistry ,Recombinant DNA ,Tumor necrosis factor alpha ,Human medicine ,lcsh:RC581-607 ,Cysteine - Abstract
Synthetic glucocorticoids (GC) are the mainstay therapy for treatment of acute and chronic inflammatory disorders. Due to the high adverse effects associated with long-term use, GC pharmacology has focused since the nineties on more selective GC ligand-binding strategies, classified as selective glucocorticoid receptor (GR) agonists (SEGRAs) or selective glucocorticoid receptor modulators (SEGRMs). In the current study, GSK866 analogs with electrophilic covalent-binding warheads were developed with potential SEGRA properties to improve their clinical safety profile for long-lasting topical skin disease applications. Since the off-rate of a covalently binding drug is negligible compared to that of a non-covalent drug, its therapeutic effects can be prolonged and typically, smaller doses of the drug are necessary to reach the same level of therapeutic efficacy, thereby potentially reducing systemic side effects. Different analogs of SEGRA GSK866 coupled to cysteine reactive warheads were characterized for GR potency and selectivity in various biochemical and cellular assays. GR- and NFκB-dependent reporter gene studies show favorable anti-inflammatory properties with reduced GR transactivation of two non-steroidal GSK866 analogs UAMC-1217 and UAMC-1218, whereas UAMC-1158 and UAMC-1159 compounds failed to modulate cellular GR activity. These results were further supported by GR immuno-localization and S211 phospho-GR western analysis, illustrating significant GR phosphoactivation and nuclear translocation upon treatment of GSK866, UAMC-1217, or UAMC-1218, but not in case of UAMC-1158 or UAMC-1159. Furthermore, mass spectrometry analysis of tryptic peptides of recombinant GR ligand-binding domain (LBD) bound to UAMC-1217 or UAMC-1218 confirmed covalent cysteine-dependent GR binding. Finally, molecular dynamics simulations, as well as glucocorticoid receptor ligand-binding domain (GR-LBD) coregulator interaction profiling of the GR-LBD bound to GSK866 or its covalently binding analogs UAMC-1217 or UAMC-1218 revealed subtle conformational differences that might underlie their SEGRA properties. Altogether, GSK866 analogs UAMC-1217 and UAMC-1218 hold promise as a novel class of covalent-binding SEGRA ligands for the treatment of topical inflammatory skin disorders.
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- 2017
38. Selective glucocorticoid receptor modulation: New directions with non-steroidal scaffolds
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Ilse M. Beck, Karolien De Bosscher, Jolien Bridelance, Claude Libert, and Nora Sundahl
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Agonist ,HUMAN OCULAR CELLS ,medicine.drug_class ,Anti-Inflammatory Agents ,Glucocorticoid receptor ,Pharmacology ,Biology ,ANTIINFLAMMATORY PROPERTIES ,Non steroidal ,TRANSCRIPTIONAL ACTIVITY ,Transactivation ,Receptors, Glucocorticoid ,Glucocorticoid Receptor Agonists ,medicine ,Medicine and Health Sciences ,Animals ,Humans ,Pharmacology (medical) ,Side effects ,RESPONSE ELEMENTS ,Glucocorticoids ,Transrepression ,GENE-EXPRESSION ,SYNOVIAL FIBROBLASTS ,Binding Sites ,COLLAGEN-INDUCED ARTHRITIS ,RHEUMATOID-ARTHRITIS ,SKELETAL-MUSCLE ATROPHY ,FACTOR-KAPPA-B ,Metabolic regulation ,Selective glucocorticoid receptor modulator ,Glucocorticoid resistance ,Glucocorticoid Resistance ,Neuroscience ,Compound A ,Immunosuppressive Agents ,Signal Transduction - Abstract
Glucocorticoids remain the frontline treatment for inflammatory disorders, yet represent a double-edged sword with beneficial therapeutic actions alongside adverse effects, mainly in metabolic regulation. Considerable efforts were made to improve this balance by attempting to amplify therapeutic beneficial anti-inflammatory actions and to minimize adverse metabolic actions. Most attention has focused on the development of novel compounds favoring the transrepressing actions of the glucocorticoid receptor, assumed to be important for anti-inflammatory actions, over the transactivating actions, assumed to underpin the undesirable actions. These compounds are classified as selective glucocorticoid receptor agonists (SEGRAs) or selective glucocorticoid receptor modulators (SEGRMs). The latter class is able to modulate the activity of a GR agonist and/or may not classically bind the glucocorticoid receptor ligand-binding pocket. SEGRAs and SEGRMs are collectively denominated SEGRAMs (selective glucocorticoid receptor agonists and modulators). Although this transrepression vs transactivation concept proved to be too simplistic, the developed SEGRAMs were helpful in elucidating various molecular actions of the glucocorticoid receptor, but have also raised many novel questions. We discuss lessons learned from recent mechanistic studies of selective glucocorticoid receptor modulators. This is approached by analyzing recent experimental insights in comparison with knowledge obtained using mutant GR research, thus clarifying the current view on the SEGRAM field. These insights also contribute to our understanding of the processes controlling glucocorticoid-mediated side effects as well as glucocorticoid resistance. Our perspective on non-steroidal SEGRAs and SEGRMs considers remaining opportunities to address research gaps in order to harness the potential for more safe and effective glucocorticoid receptor therapies.
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- 2015
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39. The role of neutrophil gelatinase associated lipocalin (NGAL) as biological constituent linking depression and cardiovascular disease
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M. Rots, Regien G. Schoemaker, Leonie Gouweleeuw, Petrus J.W. Naudé, Mike J. L. DeJongste, Ulrich L. M. Eisel, Eisel lab, and Schoemaker lab
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ACUTE MYOCARDIAL-INFARCTION ,Immunology ,Population ,ACUTE KIDNEY INJURY ,Heart failure ,Disease ,B ASSOCIATED LIPOCALIN ,Systemic inflammation ,Proinflammatory cytokine ,Behavioral Neuroscience ,Lipocalin-2 ,Neuroinflammation ,Proto-Oncogene Proteins ,Humans ,Medicine ,CORONARY-HEART-DISEASE ,Risk factor ,NGAL ,education ,Depression (differential diagnoses) ,TUMOR-NECROSIS-FACTOR ,Inflammation ,Depressive Disorder, Major ,education.field_of_study ,biology ,Endocrine and Autonomic Systems ,business.industry ,Depression ,BLOOD-BRAIN-BARRIER ,C-reactive protein ,MAJOR DEPRESSION ,Prognosis ,Cardiovascular disease ,Lipocalins ,C-REACTIVE PROTEIN ,FACTOR-KAPPA-B ,Cardiovascular Diseases ,biology.protein ,Lcn-2 ,IMMUNE-SYSTEM ,medicine.symptom ,business ,Biomarkers ,Acute-Phase Proteins - Abstract
Depression is more common in patients with cardiovascular disease than in the general population. Conversely, depression is a risk factor for developing cardiovascular disease. Comorbidity of these two pathologies worsens prognosis. Several mechanisms have been indicated in the link between cardiovascular disease and depression, including inflammation. Systemic inflammation can have long-lasting effects on the central nervous system, which could be associated with depression. NGAL is an inflammatory marker and elevated plasma levels are associated with both cardiovascular disease and depression. While patients with depression show elevated NGAL levels, in patients with comorbid heart failure, NGAL levels are significantly higher and associated with depression scores. Systemic inflammation evokes NGAL expression in the brain. This is considered a proinflammatory effect as it is involved in microglia activation and reactive astrocytosis. Animal studies support a direct link between NGAL and depression/anxiety associated behavior. In this review we focus on the role of NGAL in linking depression and cardiovascular disease.
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- 2015
40. DR4 specific TRAIL variants are more efficacious than wild-type TRAIL in pancreatic cancer
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Ralf M. Zwacka, Andrea Mohr, Stella Maris Albarenque, Wim J. Quax, Robbert H. Cool, Rui Yu, Biopharmaceuticals, Discovery, Design and Delivery (BDDD), and Nanotechnology and Biophysics in Medicine (NANOBIOMED)
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Cancer Research ,MONOCLONAL-ANTIBODY ,ANTITUMOR-ACTIVITY ,pancreatic cancer ,Gene Expression ,Apoptosis ,TRAIL ,COLORECTAL-CANCER ,TNF-Related Apoptosis-Inducing Ligand ,Mice ,Decoy receptors ,INDUCED APOPTOSIS ,CARCINOMA CELLS ,Transfection ,Recombinant Proteins ,XIAP ,Tumor Burden ,FACTOR-KAPPA-B ,Oncology ,Molecular Medicine ,Female ,DR4 specific TRAIL variant ,Research Paper ,Programmed cell death ,medicine.drug_class ,Biology ,Monoclonal antibody ,MESENCHYMAL STEM-CELLS ,Pancreatic cancer ,Cell Line, Tumor ,medicine ,Animals ,Humans ,DEATH RECEPTORS ,RECEPTOR-SELECTIVE MUTANTS ,Pharmacology ,DECOY RECEPTORS ,Genetic Variation ,medicine.disease ,Xenograft Model Antitumor Assays ,Pancreatic Neoplasms ,Disease Models, Animal ,Receptors, TNF-Related Apoptosis-Inducing Ligand ,TRAIL receptor ,Cancer cell ,Immunology ,Mutation ,Cancer research - Abstract
Current treatment modalities for pancreatic carcinoma afford only modest survival benefits. TRAIL, as a potent and specific inducer of apoptosis in cancer cells, would be a promising new treatment option. However, since not all pancreatic cancer cells respond to TRAIL, further improvements and optimizations are still needed. One strategy to improve the effectiveness of TRAIL-based therapies is to specifically target one of the 2 cell death inducing TRAIL-receptors, TRAIL-R1 or TRAIL-R2 to overcome resistance. To this end, we designed constructs expressing soluble TRAIL (sTRAIL) variants that were rendered specific for either TRAIL-R1 or TRAIL-R2 by amino acid changes in the TRAIL ectodomain. When we expressed these constructs, including wild-type sTRAIL (sTRAIL(wt)), TRAIL-R1 (sTRAIL(DR4)) and TRAIL-R2 (sTRAIL(DR5)) specific variants, in 293 producer cells we found all to be readily expressed and secreted into the supernatant. These supernatants were subsequently transferred onto target cancer cells and apoptosis measured. We found that the TRAIL-R1 specific variant had higher apoptosis-inducing activity in human pancreatic carcinoma Colo357 cells as well as PancTu1 cells that were additionally sensitized by targeting of XIAP. Finally, we tested TRAIL-R1 specific recombinant TRAIL protein (rTRAIL(DR4)) on Colo357 xenografts in nude mice and found them to be more efficacious than rTRAIL(wt). Our results demonstrate the benefits of synthetic biological approaches and show that TRAIL-R1 specific variants can potentially enhance the therapeutic efficacy of TRAIL-based therapies in pancreatic cancer, suggesting that they can possibly become part of individualized and tumor specific combination treatments in the future.
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- 2014
41. Small heterodimer partner (SHP) contributes to insulin resistance in cardiomyocytes
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Rodriguez-Calvo, Ricardo, Rodriguez-Calvo, Ricardo, Chanda, Dipanjan, Oligschlaeger, Yvonne, Miglianico, Marie, Coumans, Will A., Barroso, Emma, Tajes, Marta, Luiken, Joost J. F. P., Glatz, Jan F. C., Vazquez-Carrera, Manuel, Neumann, Dietbert, Rodriguez-Calvo, Ricardo, Rodriguez-Calvo, Ricardo, Chanda, Dipanjan, Oligschlaeger, Yvonne, Miglianico, Marie, Coumans, Will A., Barroso, Emma, Tajes, Marta, Luiken, Joost J. F. P., Glatz, Jan F. C., Vazquez-Carrera, Manuel, and Neumann, Dietbert
- Abstract
Small heterodimer partner (SHP) is an atypical nuclear receptor expressed in heart that has been shown to inhibit the hypertrophic response. Here, we assessed the role of SHP in cardiac metabolism and inflammation. Mice fed a high-fat diet (HFD) displayed glucose intolerance accompanied by increased cardiac mRNA levels of Shp. In HL-1 cardiomyocytes, SHP overexpression inhibited both basal and insulin-stimulated glucose uptake and impaired the insulin signalling pathway (evidenced by reduced ART and AS160 phosphorylation), similar to insulin resistant cells generated by high palmitate/high insulin treatment (HP/HI; 500 mu M/100 nM). In addition, SHP overexpression increased Socs3 mRNA and reduced IRS-1 protein levels. SHP overexpression also induced Cd36 expression (similar to 6.2 fold; p
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- 2017
42. Inulin-Type Fructans Modulates Pancreatic–Gut Innate Immune Responses and Gut Barrier Integrity during Experimental Acute Pancreatitis in a Chain Length-Dependent Manner
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Yue He, Chengfei Wu, Jiahong Li, Hongli Li, Zhenghua Sun, Hao Zhang, Paul de Vos, Li-Long Pan, Jia Sun, Man, Biomaterials and Microbes (MBM), and Translational Immunology Groningen (TRIGR)
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0301 basic medicine ,EXPRESSION ,lcsh:Immunologic diseases. Allergy ,medicine.medical_specialty ,medicine.medical_treatment ,pancreatic–intestinal immunity ,Immunology ,Inflammation ,NEUTROPHIL RECRUITMENT ,signaling kinases ,Biology ,dietary fibers ,pancreatic-intestinal immunity ,ACTIVATION ,03 medical and health sciences ,antimicrobial peptides ,Immune system ,Downregulation and upregulation ,Internal medicine ,medicine ,IL-10 PRODUCTION ,Immunology and Allergy ,Barrier function ,Original Research ,Innate immune system ,Correction ,SUBSTANCE-P ,FACTOR-KAPPA-B ,MICE ,030104 developmental biology ,medicine.anatomical_structure ,Endocrinology ,Cytokine ,SEVERITY ,inflammation ,tight junction proteins ,medicine.symptom ,Pancreas ,ACINAR-CELLS ,lcsh:RC581-607 ,Homeostasis - Abstract
Acute pancreatitis (AP) is a common abdominal inflammatory disorder and one of the leading causes of hospital admission for gastrointestinal disorders. No specific pharmacological or nutritional therapy is available but highly needed. Inulin-type fructans (ITFs) are capable of modifying gut immune and barrier homeostasis in a chemistry-dependent manner and hence potentially applicable for managing AP, but their efficacy in AP has not been demonstrated yet. The current study aimed to examine and compare modulatory effects of ITFs with different degrees of fermentability on pancreatic-gut immunity and barrier function during experimentally induced AP in mice. BALB/c mice were fed short (I)- or long (IV)-chain ITFs supplemented diets for up to 3 days before AP induction by caerulein. Attenuating effects on AP development were stronger with ITF IV than with ITF I. We found that long-chain ITF IV attenuated the severity of AP, as evidenced by reduced serum amylase levels, lipase levels, pancreatic myeloperoxidase activity, pancreatic edema, and histological examination demonstrating reduced pancreatic damage. Short-chain ITF I demonstrated only partial protective effects. Both ITF IV and ITF I modulated AP-associated systemic cytokine levels. ITF IV but not ITF I restored AP-associated intestinal barrier dysfunction by upregulating colonic tight junction modulatory proteins, antimicrobial peptides, and improved general colonic histology. Additionally, differential modulatory effects of ITF IV and ITF I were observed on pancreatic and gut immunity: ITF IV supplementation prevented innate immune cell infiltration in the pancreas and colon and tissue cytokine production. Similar effects were only observed in the gut with ITF I and not in the pancreas. Lastly, ITF IV but not ITF I downregulated AP-triggered upregulation of IL-1 receptor-associated kinase 4 (IRAK-4) and phosphor-c-Jun N-terminal kinase (p-JNK), and a net decrease of phosphor-nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappa B) p65 (p-NF-kappa B p65) nuclear translocation and activation in the pancreas. Our findings demonstrate a clear chain length-dependent effect of inulin on AP. The attenuating effects are caused by modulating effects of long-chain inulin on the pancreatic-gut immunity via the pancreatic IRAK-4/p-JNK/p-NF-kappa Bp65 signaling pathway and on prevention of disruption of the gut barrier.
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- 2017
43. Compound A influences gene regulation of the Dexamethasone-activated glucocorticoid receptor by alternative cofactor recruitment
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K. De Bosscher, Jonathan Thommis, Marnik Vuylsteke, Nadia Bougarne, Sofie Desmet, René Houtman, Dariusz Ratman, Jan Tavernier, L. De Cauwer, and L. Van de Moortel
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0301 basic medicine ,Receptors, Cytoplasmic and Nuclear ,Ligands ,Dexamethasone ,Mice ,Transactivation ,0302 clinical medicine ,Glucocorticoid receptor ,Gene expression ,Phosphorylation ,Receptor ,IN-VIVO ,Regulation of gene expression ,SYNOVIAL FIBROBLASTS ,Multidisciplinary ,Anti-Inflammatory Agents, Non-Steroidal ,Cell biology ,FACTOR-KAPPA-B ,030220 oncology & carcinogenesis ,Medicine ,MODULATOR COMPOUND ,Transcriptional Activation ,medicine.medical_specialty ,Science ,Biology ,Article ,MECHANISMS ,03 medical and health sciences ,Receptors, Glucocorticoid ,INFLAMMATION ,Cell Line, Tumor ,Internal medicine ,medicine ,Animals ,Humans ,Transcription factor ,Gene ,Inflammation ,LEPTIN RECEPTOR ,Leptin receptor ,COLLAGEN-INDUCED ARTHRITIS ,Biology and Life Sciences ,Epithelial Cells ,TRANSACTIVATION ,030104 developmental biology ,Endocrinology ,Gene Expression Regulation ,A549 Cells ,PLANT-ORIGIN - Abstract
The glucocorticoid receptor (GR) is a transcription factor of which the underlying gene regulatory mechanisms are complex and incompletely understood. The non-steroidal anti-inflammatory Compound A (CpdA), a selective GR modulating compound in various cell models, has been shown to favour GR-mediated gene repression but not GR-mediated gene activation. Shifting balances towards only a particular subset of GR gene regulatory events may be of benefit in the treatment of inflammatory diseases. We present evidence to support that the combination of CpdA with Dexamethasone (DEX), a classic steroidal GR ligand, can shape GR function towards a unique gene regulatory profile in a cell type-dependent manner. The molecular basis hereof is a changed GR phosphorylation status concomitant with a change in the GR cofactor recruitment profile. We subsequently identified and confirmed the orphan nuclear receptor SHP as a coregulator that is specifically enriched at GR when CpdA and DEX are combined. Combining CpdA with DEX not only leads to stronger suppression of pro-inflammatory gene expression, but also enhanced anti-inflammatory GR target gene expression in epithelial cells, making ligand combination strategies in future a potentially attractive alternative manner of skewing and fine-tuning GR effects towards an improved therapeutic benefit.
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- 2017
44. Gla-rich protein function as an anti-inflammatory agent in monocytes/macrophages
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Paula A. Videira, Dina C. Simes, Cees Vermeer, Carla Viegas, A. P. Alves de Matos, Ruben Martins Da Costa, Lúcia Santos, Nuna Araújo, Anjos L. Macedo, Zélia Silva, RS: CARIM - R1.02 - Vascular aspects thrombosis and haemostasis, and Biochemie
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Lipopolysaccharides ,0301 basic medicine ,Atherosclerotic plaques ,Physiology ,Carboxylic Acids ,Gene Expression ,Vitamin-K suppresses ,lcsh:Medicine ,Expression ,Pathology and Laboratory Medicine ,Monocytes ,White Blood Cells ,MATRIX VESICLES ,Animal Cells ,Matrix gla protein ,Medicine and Health Sciences ,Synovial macrophages ,lcsh:Science ,Immune Response ,Matrix vesicles ,Vascular calcification ,Extracellular Matrix Proteins ,Multidisciplinary ,Factor-Kappa-B ,Intracellular Signaling Peptides and Proteins ,Calcinosis ,Cell Differentiation ,Endogenous mediator ,3. Good health ,SYNOVIAL MACROPHAGES ,FACTOR-KAPPA-B ,VALVE CALCIFICATION ,Valve calcification ,Intercellular Signaling Peptides and Proteins ,Tumor necrosis factor alpha ,Cellular Types ,medicine.symptom ,hormones, hormone substitutes, and hormone antagonists ,Research Article ,Adult ,EXPRESSION ,Calcification inhibitor ,Immune Cells ,Inflammatory Diseases ,Immunology ,Inflammation ,Biology ,VITAMIN-K SUPPRESSES ,Cell Line ,Calcification ,Proinflammatory cytokine ,Extracellular Vesicles ,03 medical and health sciences ,Signs and Symptoms ,Immune system ,Diagnostic Medicine ,VASCULAR CALCIFICATION ,Osteoarthritis ,Genetics ,medicine ,Extracellular ,Humans ,ATHEROSCLEROTIC PLAQUES ,Blood Cells ,Articular-cartilage ,Macrophages ,Calcium-Binding Proteins ,lcsh:R ,Proteins ,Correction ,Biology and Life Sciences ,Cell Biology ,ARTICULAR-CARTILAGE ,030104 developmental biology ,OSTEOARTHRITIS ,Chronic Disease ,Cancer research ,biology.protein ,lcsh:Q ,Physiological Processes ,Developmental Biology - Abstract
Calcification-related chronic inflammatory diseases are multifactorial pathological processes, involving a complex interplay between inflammation and calcification events in a positive feed-back loop driving disease progression. Gla-rich protein (GRP) is a vitamin K dependent protein (VKDP) shown to function as a calcification inhibitor in cardiovascular and articular tissues, and proposed as an anti-inflammatory agent in chondrocytes and synoviocytes, acting as a new crosstalk factor between these two interconnected events in osteoarthritis. However, a possible function of GRP in the immune system has never been studied. Here we focused our investigation in the involvement of GRP in the cell inflammatory response mechanisms, using a combination of freshly isolated human leucocytes and undifferentiated/differentiated THP-1 cell line. Our results demonstrate that VKDPs such as GRP and matrix gla protein (MGP) are synthesized and gamma-carboxylated in the majority of human immune system cells either involved in innate or adaptive immune responses. Stimulation of THP-1 monocytes/macrophages with LPS or hydroxyapatite (HA) up-regulated GRP expression, and treatments with GRP or GRP-coated basic calcium phosphate crystals resulted in the down-regulation of mediators of inflammation and inflammatory cytokines, independently of the protein gamma-carboxylation status. Moreover, overexpression of GRP in THP-1 cells rescued the inflammation induced by LPS and HA, by down-regulation of the proinflammatory cytokines TNF alpha, IL-1 beta and NFkB. Interestingly, GRP was detected at protein and mRNA levels in extracellular vesicles released by macrophages, which may act as vehicles for extracellular trafficking and release. Our data indicate GRP as an endogenous mediator of inflammatory responses acting as an anti-inflammatory agent in monocytes/macrophages. We propose that in a context of chronic inflammation and calcification-related pathologies, GRP might act as a novel molecular mediator linking inflammation and calcification events, with potential therapeutic application. Portuguese Science and Technology Foundation (FCT) [PTDC/SAU-ORG/117266/2010, PTDC/BIM-MEC/1168/2012, UID/Multi/ 04326/2013]; FCT fellowships [SFRH/BPD/70277/2010, SFRH/BD/111824/2015]
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- 2017
45. Effect of interleukin (IL)-8 on benzo[a]pyrene metabolism and DNA damage in human lung epithelial cells
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Q. Shi, F.J. van Schooten, Agnes W. Boots, Guido R.M.M. Haenen, K. van Kuijk, C. Veith, L.M. Maas, Roger W. L. Godschalk, Farmacologie en Toxicologie, RS: NUTRIM - R3 - Respiratory & Age-related Health, Promovendi NTM, RS: NUTRIM - R4 - Gene-environment interaction, Ondersteunend personeel NTM, Promovendi CD, Pathologie, RS: CARIM - R3.06 - The vulnerable plaque: makers and markers, RS: CARIM - R2.03 - ECM + Wnt signaling, and RS: NUTRIM - R3 - Chronic inflammatory disease and wasting
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0301 basic medicine ,1B1 (CYP1A1/CYP1B1) ,AIRWAY INFLAMMATION ,Metabolite ,medicine.medical_treatment ,Mutagen ,NADPH oxidase pathway (NOX) ,Toxicology ,medicine.disease_cause ,chemistry.chemical_compound ,TRANSCRIPTION FACTOR ,OXIDATIVE STRESS ,Lung ,GENE-EXPRESSION ,biology ,FACTOR-KAPPA-B ,Cytokine ,Benzo(a)pyrene ,Biochemistry ,Interleukin (IL)-8 ,Cytochrome P-450 CYP1B1 ,Intracellular ,Glutathione (GSH) ,Cell Survival ,DNA damage ,OBSTRUCTIVE PULMONARY-DISEASE ,Cell Line ,NADPH-dependent cytochrome P450s 1A1 ,POLYCYCLIC AROMATIC-HYDROCARBONS ,03 medical and health sciences ,Cytochrome P-450 CYP1A1 ,medicine ,Humans ,RNA, Messenger ,Benzo[a]pyrene (B[a]P) ,Interleukin-8 ,INFLAMMATORY RESPONSE ,NADPH Oxidases ,Cytochrome P450 ,DNA adducts ,Epithelial Cells ,Glutathione ,ADDUCT LEVELS ,Molecular biology ,030104 developmental biology ,chemistry ,NUCLEOTIDE EXCISION-REPAIR ,Carcinogens ,biology.protein ,NADP ,DNA Damage - Abstract
It has been well established that inflammation and concurrent mutagenic exposures drive the carcinogenic process in a synergistic way. To elucidate the role of the inflammatory cytokine IL-8 in this process, we studied its effect on the activation and deactivation of the chemical mutagen benzo[a]pyrene B[a]P in the immortalized pulmonary BEAS-2B cell line. After 24 h incubation with B[a]P in the presence or absence of IL-8, the B[a]P induced cytochrome P450 1A1 and 1B1 (CYP1A1 and CYP1B1) gene expression and CYP1A1 enzyme activity was significantly higher in the presence of the cytokine. Consistent with these findings, we observed higher concentration of the metabolite B[a]P-7,8-diol under concurrent IL-8 treatment conditions. Interestingly, we also found higher concentrations of unmetabolized B[a]P. To explain this, we examined the downstream effects of IL-8 on NADPH oxidases (NOXes). IL-8 lowered the intracellular NADPH level, but this effect could not explain the changes in B[a]P metabolism. IL-8 also significantly depleted intracellular glutathione (GSH), which also resulted in enhanced levels of unmetabolized B[a]P, but increased concentrations of the metabolite B[a]P-7,8-diol. No differences in B[a]P-DNA adducts level were found between B[a]P and B[a]P combined with IL-8, and this might be due to a 3-fold increase in nucleotide excision repair (NER) after IL-8 treatment. These findings suggest that IL-8 increased the formation of B[a]P-7,8-diol despite an overall delayed B[a]P metabolism via depletion of GSH, but DNA damage levels were unaffected due to an increase in NER capacity. (C) 2017 Elsevier B.V. All rights reserved.
- Published
- 2017
46. Highly polygenic architecture of antidepressant treatment response: Comparative analysis of SSRI and NRI treatment in an animal model of depression
- Author
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Malki, Karim, Tosto, Maria Grazia, Mouriño-Talín, Héctor, Rodríguez-Lorenzo, Sabela, Pain, Oliver, Jumhaboy, Irfan, Liu, Tina, Parpas, Panos, Newman, Stuart, Malykh, Arten, Carboni, Lucia, Uher, Rudolf, McGuffin, Peter, Schalkwyk, Leonard C., Bryson, Kevin, Herbster, Mark, Malki, Karim, Tosto, Maria Grazia, Mouriño-Talín, Héctor, Rodríguez-Lorenzo, Sabela, Pain, Oliver, Jumhaboy, Irfan, Liu, Tina, Parpas, Pano, Newman, Stuart, Malykh, Artem, Carboni, Lucia, Uher, Rudolf, Mcguffin, Peter, Schalkwyk, Leonard C., Bryson, Kevin, Herbster, Mark, and Engineering & Physical Science Research Council (EPSRC)
- Subjects
Male ,Multifactorial Inheritance ,SVM ,Antidepressant ,Nortriptyline ,Citalopram ,Hippocampus ,HIPPOCAMPAL NEUROGENESIS ,CANDIDATE GENES ,transcriptomics ,Mice ,Cellular and Molecular Neuroscience ,Machine learning ,WIDE ASSOCIATION ,FACTOR CREB ,Animals ,SSRI ,Serotonin and Noradrenaline Reuptake Inhibitors ,Cyclic AMP Response Element-Binding Protein ,Research Articles ,Genetics (clinical) ,Genetics & Heredity ,Psychiatry ,Depressive Disorder ,0604 Genetics ,Science & Technology ,DRUG-TREATMENT ,CONVERGENT FUNCTIONAL GENOMICS ,MOLECULAR-MECHANISMS ,Depression ,1103 Clinical Sciences ,MAJOR DEPRESSION ,ELEMENT-BINDING PROTEIN ,Antidepressive Agents ,FACTOR-KAPPA-B ,Disease Models, Animal ,Treatment Outcome ,Transcriptomic ,Pharmacogenetics ,Psychiatry and Mental Health ,antidepressants ,Serotonin Uptake Inhibitors ,Female ,Transcriptome ,1109 Neurosciences ,Life Sciences & Biomedicine ,Selective Serotonin Reuptake Inhibitors ,Research Article - Abstract
Response to antidepressant (AD) treatment may be a more polygenic trait than previously hypothesized, with many genetic variants interacting in yet unclear ways. In this study we used methods that can automatically learn to detect patterns of statistical regularity from a sparsely distributed signal across hippocampal transcriptome measurements in a large‐scale animal pharmacogenomic study to uncover genomic variations associated with AD. The study used four inbred mouse strains of both sexes, two drug treatments, and a control group (escitalopram, nortriptyline, and saline). Multi‐class and binary classification using Machine Learning (ML) and regularization algorithms using iterative and univariate feature selection methods, including InfoGain, mRMR, ANOVA, and Chi Square, were used to uncover genomic markers associated with AD response. Relevant genes were selected based on Jaccard distance and carried forward for gene‐network analysis. Linear association methods uncovered only one gene associated with drug treatment response. The implementation of ML algorithms, together with feature reduction methods, revealed a set of 204 genes associated with SSRI and 241 genes associated with NRI response. Although only 10% of genes overlapped across the two drugs, network analysis shows that both drugs modulated the CREB pathway, through different molecular mechanisms. Through careful implementation and optimisations, the algorithms detected a weak signal used to predict whether an animal was treated with nortriptyline (77%) or escitalopram (67%) on an independent testing set. The results from this study indicate that the molecular signature of AD treatment may include a much broader range of genomic markers than previously hypothesized, suggesting that response to medication may be as complex as the pathology. The search for biomarkers of antidepressant treatment response could therefore consider a higher number of genetic markers and their interactions. Through predominately different molecular targets and mechanisms of action, the two drugs modulate the same Creb1 pathway which plays a key role in neurotrophic responses and in inflammatory processes. © 2016 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics Published by Wiley Periodicals, Inc.
- Published
- 2017
47. Transfer factor for carbon monoxide in patients with COPD and diabetes
- Subjects
METFORMIN ,MORTALITY ,Diabetes ,OBSTRUCTIVE PULMONARY-DISEASE ,Lung function ,REFERENCE VALUES ,CAPACITY ,LUNG-FUNCTION ,FACTOR-KAPPA-B ,MELLITUS ,INFLAMMATION ,COPD ,MACROPHAGES ,Diffusing capacity - Abstract
Background: An impairment of CO diffusing capacity has been shown in diabetic patients without lung disease. We analyzed how diffusing capacity in patients with COPD is affected by the concurrent diagnosis of diabetes. Methods: Data from the initial visit of the German COPD cohort COSYCONET were used for analysis. 2575 patients with complete lung function data were included, among them 358 defined as diabetics with a reported physician diagnosis of diabetes and/or specific medication. Pairwise comparisons between groups and multivariate regression models were used to identify variables predicting the CO transfer factor (TLCO% pred) and the transfer coefficient (KCO% pred). Results: COPD patients with diabetes differed from those without diabetes regarding lung function, anthropometric, clinical and laboratory parameters. Moreover, gender was an important covariate. After correction for lung function, gender and body mass index (BMI), TLCO% pred did not significantly differ between patients with and without diabetes. The results for the transfer coefficient KCO were similar, demonstrating an important role of the confounding factors RV% pred, TLC% pred, ITGV% pred, FEV1% pred, FEV1/FVC, age, packyears, creatinine and BMI. There was not even a tendency towards lower values in diabetes. Conclusion: The analysis of data from a COPD cohort showed no significant differences of CO transport parameters between COPD patients with and without diabetes, if BMI, gender and the reduction in lung volumes were taken into account. This result is in contrast to observations in lung-healthy subjects with diabetes and raises the question which factors, among them potential anti-inflammatory effects of anti-diabetes medication are responsible for this finding.
- Published
- 2017
48. Transfer factor for carbon monoxide in patients with COPD and diabetes: results from the German COSYCONET cohort
- Author
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Kahnert, Kathrin, Lucke, Tanja, Biertz, Frank, Lechner, Andreas, Watz, Henrik, Alter, Peter, Bals, Robert, Behr, Jürgen, Holle, Rolf, Huber, Rudolf M., Karrasch, Stefan, Stubbe, Beate, Wacker, Margarethe, Söhler, Sandra, Wouters, Emiel F. M., Vogelmeier, Claus, Jörres, Rudolf A., MUMC+: MA Longziekten (3), RS: NUTRIM - R3 - Respiratory & Age-related Health, Pulmonologie, and RS: NUTRIM - R3 - Chronic inflammatory disease and wasting
- Subjects
Pulmonary and Respiratory Medicine ,Male ,METFORMIN ,Comorbidity ,Sensitivity and Specificity ,OBSTRUCTIVE PULMONARY-DISEASE ,CAPACITY ,Cohort Studies ,Pulmonary Disease, Chronic Obstructive ,MELLITUS ,INFLAMMATION ,Risk Factors ,Germany ,Diabetes Mellitus ,Prevalence ,Humans ,COPD ,MACROPHAGES ,Aged ,Diffusing capacity ,Carbon Monoxide ,Research ,MORTALITY ,Diabetes ,Reproducibility of Results ,respiratory system ,Carbon Dioxide ,Middle Aged ,Lung function ,REFERENCE VALUES ,respiratory tract diseases ,LUNG-FUNCTION ,FACTOR-KAPPA-B ,Copd ,Diffusing Capacity ,Lung Function ,Pulmonary Diffusing Capacity ,Female - Abstract
Background: An impairment of CO diffusing capacity has been shown in diabetic patients without lung disease. We analyzed how diffusing capacity in patients with COPD is affected by the concurrent diagnosis of diabetes. Methods: Data from the initial visit of the German COPD cohort COSYCONET were used for analysis. 2575 patients with complete lung function data were included, among them 358 defined as diabetics with a reported physician diagnosis of diabetes and/or specific medication. Pairwise comparisons between groups and multivariate regression models were used to identify variables predicting the CO transfer factor (TLCO% pred) and the transfer coefficient (KCO% pred). Results: COPD patients with diabetes differed from those without diabetes regarding lung function, anthropometric, clinical and laboratory parameters. Moreover, gender was an important covariate. After correction for lung function, gender and body mass index (BMI), TLCO% pred did not significantly differ between patients with and without diabetes. The results for the transfer coefficient KCO were similar, demonstrating an important role of the confounding factors RV% pred, TLC% pred, ITGV% pred, FEV1% pred, FEV1/FVC, age, packyears, creatinine and BMI. There was not even a tendency towards lower values in diabetes. Conclusion: The analysis of data from a COPD cohort showed no significant differences of CO transport parameters between COPD patients with and without diabetes, if BMI, gender and the reduction in lung volumes were taken into account. This result is in contrast to observations in lung-healthy subjects with diabetes and raises the question which factors, among them potential anti-inflammatory effects of anti-diabetes medication are responsible for this finding.
- Published
- 2017
49. DRD2: Bridging the Genome and Ingestive Behavior
- Author
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Xue Sun, Dana M. Small, Serge Luquet, Unité de Biologie Fonctionnelle et Adaptative (BFA (UMR_8251 / U1133)), and Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
- Subjects
0301 basic medicine ,HIGH-FAT DIET ,Cognitive Neuroscience ,Dopamine ,[SDV]Life Sciences [q-bio] ,Brain Structure and Function ,Diet and obesity ,Alpha-Ketoglutarate-Dependent Dioxygenase FTO ,Experimental and Cognitive Psychology ,Protein Serine-Threonine Kinases ,Article ,Developmental psychology ,03 medical and health sciences ,0302 clinical medicine ,WORKING-MEMORY ,D2 RECEPTOR ,medicine ,Humans ,Genetic Predisposition to Disease ,Obesity ,Cognitive decline ,Overeating ,FTO GENE ,ANKK1 ,GENETICALLY-DETERMINED DIFFERENCES ,Receptors, Dopamine D2 ,Cognition ,DOPAMINE-RECEPTOR GENE ,WEIGHT-GAIN ,BODY-MASS INDEX ,FACTOR-KAPPA-B ,ENERGY-INTAKE ,030104 developmental biology ,Neuropsychology and Physiological Psychology ,Gene-Environment Interaction ,Psychology ,Neuroscience ,Neurocognitive ,030217 neurology & neurosurgery ,medicine.drug - Abstract
International audience; Recent work highlights the importance of genetic variants that influence brain structure and function in conferring risk for polygenic obesity. The neurotransmitter dopamine (DA) has a pivotal role in energy balance by integrating metabolic signals with circuits supporting cognitive, perceptual, and appetitive functions that guide feeding. It has also been established that diet and obesity alter DA signaling, leading to compulsive-like feeding and neurocognitive impairments. This raises the possibility that genetic variants that influence DA signaling and adaptation confer risk for overeating and cognitive decline. Here, we consider the role of two common gene variants, FTO and TaqIA rs1800497 in driving gene x environment interactions promoting obesity, metabolic dysfunction, and cognitive change via their influence on DA receptor subtype 2 (DRD2) signaling.
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- 2017
50. Type I Interferons as Regulators of Lung Inflammation
- Author
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Cecilia Johansson, Spyridon Makris, Michelle Paulsen, Medical Research Council (MRC), Rosetrees Trust, and National Heart and Lung Institute Foundation
- Subjects
0301 basic medicine ,medicine.medical_treatment ,Immunology ,RESPIRATORY SYNCYTIAL VIRUS ,Inflammation ,Review ,CD8(+) T-CELLS ,Biology ,lung ,RIG-I ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Interferon ,Immunopathology ,medicine ,PATTERN-RECOGNITION RECEPTORS ,Immunology and Allergy ,TOLL-LIKE RECEPTORS ,Science & Technology ,INNATE IMMUNE GENES ,Pattern recognition receptor ,pattern recognition receptors ,CYCLIC GMP-AMP ,infection ,3. Good health ,FACTOR-KAPPA-B ,030104 developmental biology ,Cytokine ,Viral replication ,type I interferons ,inflammation ,PLASMACYTOID DENDRITIC CELLS ,medicine.symptom ,Life Sciences & Biomedicine ,CYTOSOLIC DNA ,030215 immunology ,medicine.drug - Abstract
Immune responses to lung infections must be tightly regulated in order to permit pathogen eradication while maintaining organ function. Exuberant or dysregulated inflammation can impair gas exchange and underlies many instances of lung disease. An important driver of inflammation in the lung is the interferon (IFN) response. Type I IFNs are anti-viral cytokines that induce a large range of proteins that impair viral replication in infected cells. This cell-intrinsic action plays a crucial role in protecting the lungs from spread of respiratory viruses. However, type I IFNs have also recently been found to be central to the initiation of lung inflammatory responses, by inducing recruitment and activation of immune cells. This helps control virus burden but can cause detrimental immunopathology and contribute to disease severity. Furthermore, there is now increasing evidence that type I IFNs are not only induced after viral infections but also after infection with bacteria and fungi. The pro-inflammatory function of type I IFNs in the lung opens up the possibility of immune modulation directed against this anti-viral cytokine family. In this review, the initiation and signaling of type I IFNs as well as their role in driving and maintaining lung inflammation will be discussed.
- Published
- 2016
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