97 results on '"Secher T"'
Search Results
2. Mucosal administration of anti-bacterial antibody (Ab) provides long-term cross-protection against Pseudomonas aeruginosa respiratory infection
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Pitiot, A, primary, Ferreira, M, additional, Parent, C, additional, Boisseau, C, additional, Cortes, M, additional, Bouvart, L, additional, Aubrey, N, additional, Paget, C, additional, Heuzé-Vourc'H, N, additional, and Secher, T, additional
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- 2022
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3. Inhalation of an immunomodulatory adjuvant to treat drug-resistant bacterial pneumonia
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Pardessus, J., Guillot, L., Mayor, A., Baldry, M., Michelet, R., Cayet, D., Cabrera, M., Le Pennec, D., Secher, T., Aulin, L.B.S., Kloft, C., MacLoughlin, R., Sirard, J.C., and Heuzé-Vourc’h, N.
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- 2024
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4. Mucosal administration of an immunotherapy provides long-term protection against a bacterial respiratory infection
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Pitiot, A., Ferreira, M., Parent, C., Boisseau, C., Cortes, M., Bouvart, L., Paget, C., Heuzé-Vourc’h, N., and Sécher, T.
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- 2024
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5. Toll-like receptor 2 is critical for induction of Reg3(beta) expression and intestinal clearance of Yersinia pseudotuberculosis
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Dessein, R., Gironella, M., Vignal, C., Peyrin-Biroulet, L., Sokol, H., Secher, T., Lacas-Gervais, S., Gratadoux, J.-J., Lafont, F., Dagorn, J.-C., Ryffel, B., Akira, S., Langella, P., Nunez, G., Sirard, J.-C., Iovanna, J., Simonet, M., and Chamaillard, M.
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Cell receptors -- Genetic aspects ,Cell receptors -- Physiological aspects ,Cell receptors -- Research ,Gene expression -- Research ,Pseudotuberculosis -- Complications and side effects ,Pseudotuberculosis -- Prevention ,Pseudotuberculosis -- Research ,Cellular signal transduction -- Physiological aspects ,Cellular signal transduction -- Research ,Health - Published
- 2009
6. Anti-Pseudomonas aeruginosa serotype O11 LPS immunoglobulin M monoclonal antibody panobacumab (KBPA101) confers protection in a murine model of acute lung infection
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Secher, T., Fauconnier, L., Szade, A., Rutschi, O., Fas, S. C., Ryffel, B., and Rudolf, M. P.
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- 2011
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7. The PPAR target gene CD36 is a rate limiting factor for the sensing of gram positive S. aureus in vascular smooth muscle cells but not in macrophages: C057
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Moreno, L, McMaster, S K, Paul-Clark, M, Harrington, L, Cartwright, N, Secher, T, Quesniaux, V, Ryffel, B, and Mitchell, J A
- Published
- 2008
8. Impairment of glutamatergic neurons in the prefrontal cortex by means of phencyclidine therapeutic approaches: W2–04
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BEREZIN, V., SECHER, T., GLENTHØ, J. B., and BOCK, E.
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- 2007
9. Inhibitors of retrograde trafficking active against ricin and Shiga toxins also protect cells from several viruses, Chlamydiales and Leishmania
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Gupta, N., Noël, R., Goudet, A., Hinsinger, K., Michau, A., Pons, V., Abdelkafi, H., Secher, T., Shima, A., Shtanko, O., Sakurai, Y., Cojean, S., Pomel, S., Liévin-le Moal, V., Leignel, V., Herweg, J.-a., Fischer, A., Johannes, L., Harrison, Kate, Beard, Philippa M., Clayette, P., Le Grand, R., Rayner, J.o., Rudel, T., Vacus, J., Loiseau, P.m., Davey, R.a., Oswald, E., Cintrat, J.-c., Barbier, J., and Gillet, D.
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Emerging infectious diseases ,endocrine system ,Biothreat agents ,Ricin toxin ,High-throughput cell-based assays ,Retrograde cell transport ,Shiga-like toxins ,Bioterrorism - Abstract
Medical countermeasures to treat biothreat agent infections require broad-spectrum therapeutics that do not induce agent resistance. A cell-based high-throughput screen (HTS) against ricin toxin combined with hit optimization allowed selection of a family of compounds that meet these requirements. The hit compound Retro-2 and its derivatives have been demonstrated to be safe in vivo in mice even at high doses. Moreover, Retro-2 is an inhibitor of retrograde transport that affects syntaxin-5-dependent toxins and pathogens. As a consequence, it has a broad-spectrum activity that has been demonstrated both in vitro and in vivo against ricin, Shiga toxin-producing O104:H4 entero-hemorrhagic E. coli and Leishmania sp. and in vitro against Ebola, Marburg and poxviruses and Chlamydiales. An effect is anticipated on other toxins or pathogens that use retrograde trafficking and syntaxin-5. Since Retro-2 targets cell components of the host and not directly the pathogen, no selection of resistant pathogens is expected. These lead compounds need now to be developed as drugs for human use.
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- 2017
10. Low-field magnetic resonance imaging of the lumbar spine: reliability of qualitative evaluation of disc and muscle parameters
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Secher T. Jensen, Poul Erik Andersen, Solgaard J. Sorensen, and Per Kjaer
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Adult ,Male ,medicine.medical_specialty ,Population ,Lumbar vertebrae ,Lumbar ,Muscular Diseases ,medicine ,Humans ,Radiology, Nuclear Medicine and imaging ,education ,Grading (tumors) ,Observer Variation ,Reproducibility ,education.field_of_study ,Lumbar Vertebrae ,Radiological and Ultrasound Technology ,medicine.diagnostic_test ,business.industry ,Reproducibility of Results ,Magnetic resonance imaging ,General Medicine ,Magnetic Resonance Imaging ,Intervertebral disk ,medicine.anatomical_structure ,Female ,Lumbar spine ,Radiology ,business ,Intervertebral Disc Displacement - Abstract
Purpose: To determine the intra- and interobserver reliability in grading disc and muscle parameters using low-field magnetic resonance imaging (MRI). Material and Methods: MRI scans of 100 subjects representative of the general population were evaluated blindly by two radiologists. Criteria for grading lumbar discs were based on the spinal nomenclature of the Combined Task Force and the literature. Consensus in rating was achieved by evaluating 50 MRI examinations in tandem. The remaining 50 examinations were evaluated independently by the observers to determine interobserver agreement and re-evaluated by one of the observers to determine intra-observer agreement. Results: Intra- and interobserver agreement was substantial when grading changes in the lumbar discs. Interobserver agreement was fair to moderate in grading the lumbar muscles, whereas intra-observer agreement was almost perfect. Conclusion: Convincing reliability was found in the evaluation of disc- and muscle-related MRI variables.
- Published
- 2006
11. Mu and delta opioid receptor knockout mice show increased colonic sensitivity
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Reiss, D., primary, Ceredig, R.A., additional, Secher, T., additional, Boué, J., additional, Barreau, F., additional, Dietrich, G., additional, and Gavériaux-Ruff, C., additional
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- 2016
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12. Inhibitors of intracellular trafficking active against shiga toxin and ricin
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Gupta, N., primary, Noël, R., additional, Michau, A., additional, Hinsinger, K., additional, Pons, V., additional, Shima, A., additional, Secher, T., additional, Garcia-Castillo, D., additional, Johannes, L., additional, Oswald, E., additional, Cintrat, J.-C., additional, Barbier, J., additional, and Gillet, D., additional
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- 2016
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13. Retrograde Trafficking Inhibitor of Shiga Toxins Reduces Morbidity and Mortality of Mice Infected with Enterohemorrhagic Escherichia coli
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Secher, T., primary, Shima, A., additional, Hinsinger, K., additional, Cintrat, J. C., additional, Johannes, L., additional, Barbier, J., additional, Gillet, D., additional, and Oswald, E., additional
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- 2015
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14. Mu and delta opioid receptor knockout mice show increased colonic sensitivity.
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Reiss, D., Ceredig, R.A., Secher, T., Boué, J., Barreau, F., Dietrich, G., and Gavériaux ‐ Ruff, C.
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PAIN management ,ANALGESICS ,ANIMAL experimentation ,ANIMALS ,CELL receptors ,COLITIS ,DEXTRAN ,ENKEPHALINS ,INTERLEUKIN-1 ,MICE ,NARCOTICS ,OPIOID peptides ,PAIN ,PROTEIN precursors ,TUMOR necrosis factors ,PHARMACODYNAMICS - Abstract
Background: Opiates act through opioid receptors to diminish pain. Here, we investigated whether mu (MOR) and delta (DOR) receptor endogenous activity assessed in the whole mouse body or in particular at peripheral receptors on primary nociceptive neurons, control colonic pain.Methods: We compared global MOR and DOR receptor knockout (KO) mice, mice with a conditional deletion of MOR and DOR in Nav1.8-positive nociceptive primary afferent neurons (cKO), and control floxed mice of both genders for visceral sensitivity. Visceromotor responses to colorectal distension (CRD) and macroscopic colon scores were recorded on naïve mice and mice with acute colitis induced by 3% dextran sodium sulphate (DSS) for 5 days. Transcript expression for opioid genes and cytokines was measured by quantitative RT-PCR.Results: Naïve MOR and DOR global KO mice show increased visceral sensitivity that was not observed in cKO mice. MOR and preproenkephalin (Penk) were the most expressed opioid genes in colon. MOR KO mice had augmented kappa opioid receptor and Tumour-Necrosis-Factor-α and diminished Penk transcript levels while DOR, preprodynorphin and Interleukin-1β were unchanged. Global MOR KO females had a thicker colon than floxed females. No alteration was detected in DOR mutant animals. A 5-day DSS treatment led to comparable hypersensitivity in the different mouse lines.Conclusion: Our results suggest that mu and delta opioid receptor global endogenous activity but not activity at the peripheral Nav1.8 neurons contribute to visceral sensitivity in naïve mice, and that endogenous MOR and DOR tones were insufficient to elicit analgesia after 5-day DSS-induced colitis.Significance: Knockout mice for mu and delta opioid receptor have augmented colon sensitivity in the CRD assay. It shows endogenous mu and delta opioid analgesia that may be explored as potential targets for alleviating chronic intestinal pain. [ABSTRACT FROM AUTHOR]- Published
- 2017
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15. IL-33 targeting attenuates intestinal mucositis and enhances effective tumor chemotherapy in mice
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Guabiraba, R, primary, Besnard, A G, additional, Menezes, G B, additional, Secher, T, additional, Jabir, M S, additional, Amaral, S S, additional, Braun, H, additional, Lima-Junior, R CP, additional, Ribeiro, R A, additional, Cunha, F Q, additional, Teixeira, M M, additional, Beyaert, R, additional, Graham, G J, additional, and Liew, F Y, additional
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- 2014
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16. S.4.01 Neuroplasticity and neuronal cell adhesion molecules
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Bock, E., Walmod, P.S., Secher, T., and Berezin, V.
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- 2009
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17. Enhancement of Methacholine-Evoked Tracheal Contraction Induced by Bacterial Lipopolysaccharides Depends on Epithelium and Tumor Necrosis Factor
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Secher, T., primary, Rodrigues Coelho, F., additional, Noulin, N., additional, Lino dos Santos Franco, A., additional, Quesniaux, V., additional, Lignon, J., additional, Mitchell, J., additional, Moser, R., additional, Gomes, E., additional, Mirotti, L., additional, Tavares-de-Lima, W., additional, Ryffel, B., additional, Vargaftig, B. Boris, additional, and Russo, M., additional
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- 2012
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18. Low-field magnetic resonance imaging of the lumbar spine: reliability of qualitative evaluation of disc and muscle parameters
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Sorensen, Solgaard J., primary, Kjaer, P., additional, Jensen, Secher T., additional, and Andersen, P., additional
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- 2006
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19. A neural cell adhesion molecule–derived fibroblast growth factor receptor agonist, the FGL-peptide, promotes early postnatal sensorimotor development and enhances social memory retention
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Secher, T., primary, Novitskaia, V., additional, Berezin, V., additional, Bock, E., additional, Glenthøj, B., additional, and Klementiev, B., additional
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- 2006
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20. Shared and Distinct Renal Transcriptome Signatures in 3 Standard Mouse Models of Chronic Kidney Disease.
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Marstrand-Jørgensen AB, Sembach FE, Bak ST, Ougaard M, Christensen-Dalsgaard M, Rønn Madsen M, Jensen DM, Secher T, Heimbürger SMN, Fink LN, Hansen D, Hansen HH, Østergaard MV, Christensen M, and Dalbøge LS
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- Animals, Male, Mice, Fibrosis, Ureteral Obstruction genetics, Ureteral Obstruction complications, Reperfusion Injury genetics, Transcriptome, Mice, Inbred C57BL, Disease Models, Animal, Renal Insufficiency, Chronic genetics, Renal Insufficiency, Chronic pathology, Kidney pathology, Kidney metabolism
- Abstract
Introduction: Several mouse models with diverse disease etiologies are used in preclinical research for chronic kidney disease (CKD). Here, we performed a head-to-head comparison of renal transcriptome signatures in standard mouse models of CKD to assess shared and distinct molecular changes in three mouse models commonly employed in preclinical CKD research and drug discovery., Methods: All experiments were conducted on male C57BL/6J mice. Mice underwent sham, unilateral ureter obstruction (UUO), or unilateral ischemic-reperfusion injury (uIRI) surgery and were terminated two- and 6-weeks post-surgery, respectively. The adenine-supplemented diet-induced (ADI) model of CKD was established by feeding with adenine diet for 6 weeks and compared to control diet feeding. For all models, endpoints included plasma biochemistry, kidney histology, and RNA sequencing., Results: All models displayed increased macrophage infiltration (F4/80 IHC) and fibrosis (collagen 1a1 IHC). Compared to corresponding controls, all models were characterized by an extensive number of renal differentially expressed genes (≥11,000), with a notable overlap in transcriptomic signatures across models. Gene expression markers of fibrosis, inflammation, and kidney injury supported histological findings. Interestingly, model-specific transcriptome signatures included several genes representing current drug targets for CKD, emphasizing advantages and limitations of the three CKD models in preclinical target and drug discovery., Conclusion: The UUO, uIRI, and ADI mouse models of CKD have significant commonalities in their renal global transcriptome profile. Model-specific renal transcriptional signatures should be considered when selecting the specific model in preclinical target and drug discovery., (© 2024 S. Karger AG, Basel.)
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- 2024
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21. A Protective Role of NOD2 on Oxazolone-induced Intestinal Inflammation Through IL-1β-mediated Signalling Pathway.
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Secher T, Couturier A, Huot L, Bouscayrol H, Grandjean T, Boulard O, Hot D, Ryffel B, and Chamaillard M
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- Mice, Animals, Acetylmuramyl-Alanyl-Isoglutamine adverse effects, Acetylmuramyl-Alanyl-Isoglutamine metabolism, Inflammation, Signal Transduction, Nod2 Signaling Adaptor Protein genetics, Nod2 Signaling Adaptor Protein metabolism, Oxazolone adverse effects, Colitis metabolism
- Abstract
Background and Aims: NOD2 has emerged as a critical player in the induction of both Th1 and Th2 responses for potentiation and polarisation of antigen-dependent immunity. Loss-of-function mutations in the NOD2-encoding gene and deregulation of its downstream signalling pathway have been linked to Crohn's disease. Although it is well documented that NOD2 is capable of sensing bacterial muramyl dipeptide, it remains counter-intuitive to link development of overt intestinal inflammation to a loss of bacterial-induced inflammatory response. We hypothesised that a T helper bias could also contribute to an autoimmune-like colitis different from inflammation that is fully fledged by Th1 type cells., Methods: An oedematous bowel wall with a mixed Th1/Th2 response was induced in mice by intrarectal instillation of the haptenating agent oxazolone. Survival and clinical scoring were evaluated. At several time points after instillation, colonic damage was assessed by macroscopic and microscopic observations. To evaluate the involvement of NOD2 in immunochemical phenomena, quantitative polymerase chain reaction [PCR] and flow cytometry analysis were performed. Bone marrow chimera experimentation allowed us to evaluate the role of haematopoietic/non-hematopoietic NOD2-expressing cells., Results: Herein, we identified a key regulatory circuit whereby NOD2-mediated sensing of a muramyl dipeptide [MDP] by radio-resistant cells improves colitis with a mixed Th1/Th2 response that is induced by oxazolone. Genetic ablation of either Nod2 or Ripk2 precipitated oxazolone colitis that is predominantly linked to a lack of interferon-gamma. Bone marrow chimera experiments revealed that inactivation of Nod2 signalling in non-haematopoietic cells is causing a biased M1-M2 polarisation of macrophages and a decreased frequency of splenic regulatory T cells that correlates with an impaired activation of CD4 + T cells within mesenteric lymph nodes. Mechanistically, mice were protected from oxazolone-induced colitis upon administration of MDP in an interleukin-1- and interleukin-23-dependent manner., Conclusions: These findings indicate that Nod2 signalling may prevent pathological conversion of T helper cells for maintenance of tissue homeostasis., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
- Published
- 2023
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22. Oral supplementation with yeast β -glucans improves the resolution of Escherichia coli -associated inflammatory responses independently of monocyte/macrophage immune training.
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Walachowski S, Breyne K, Secher T, Cougoule C, Guzylack-Piriou L, Meyer E, Foucras G, and Tabouret G
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- Mice, Animals, Saccharomyces cerevisiae, Escherichia coli, Monocytes, Macrophages, Cytokines, beta-Glucans pharmacology, Yeast, Dried
- Abstract
Introduction: Confronted with the emerging threat of antimicrobial resistance, the development of alternative strategies to limit the use of antibiotics or potentiate their effect through synergy with the immune system is urgently needed. Many natural or synthetic biological response modifiers have been investigated in this context. Among them, β-glucans, a type of soluble or insoluble polysaccharide composed of a linear or branched string of glucose molecules produced by various cereals, bacteria, algae, and inferior (yeast) and superior fungi (mushrooms) have garnered interest in the scientific community, with not less than 10,000 publications over the last two decades. Various biological activities of β-glucans have been reported, such as anticancer, antidiabetic and immune-modulating effects. In vitro, yeast β-glucans are known to markedly increase cytokine secretion of monocytes/macrophages during a secondary challenge, a phenomenon called immune training., Methods: Here, we orally delivered β-glucans derived from the yeast S. cerevisiae to mice that were further challenged with Escherichia coli., Results: β-glucan supplementation protected the mice from E. coli intraperitoneal and intra-mammary infections, as shown by a lower bacterial burden and greatly diminished tissue damage. Surprisingly, this was not associated with an increased local immune response. In addition, granulocyte recruitment was transient and limited, as well as local cytokine secretion, arguing for faster resolution of the inflammatory response. Furthermore, ex-vivo evaluation of monocytes/macrophages isolated or differentiated from β-glucan-supplemented mice showed these cells to lack a trained response versus those from control mice., Conclusion: In conclusion, dietary β-glucans can improve the outcome of Escherichia coli infections and dampen tissue damages associated to excessive inflammatory response. The mechanisms associated with such protection are not necessarily linked to immune system hyper-activation or immune training., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Walachowski, Breyne, Secher, Cougoule, Guzylack-Piriou, Meyer, Foucras and Tabouret.)
- Published
- 2022
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23. Nephroprotective Effects of Semaglutide as Mono- and Combination Treatment with Lisinopril in a Mouse Model of Hypertension-Accelerated Diabetic Kidney Disease.
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Dalbøge LS, Christensen M, Madsen MR, Secher T, Endlich N, Drenic' V, Manresa-Arraut A, Hansen HH, Rune I, Fink LN, and Østergaard MV
- Abstract
Background : Obesity, hyperglycemia and hypertension are critical risk factors for development of diabetic kidney disease (DKD). Emerging evidence suggests that glucagon-like peptide-1 receptor (GLP-1R) agonists improve cardiovascular and renal outcomes in type 2 diabetes patients. Here, we characterized the effect of the long-acting GLP-1R agonist semaglutide alone and in combination with an ACE inhibitor (lisinopril) in a model of hypertension-accelerated, advanced DKD facilitated by adeno-associated virus-mediated renin overexpression (ReninAAV) in uninephrectomized (UNx) female diabetic db / db mice. Methods : Female db / db mice received a single intravenous injection of ReninAAV 1 week prior to UNx. Six weeks post-nephrectomy, db / db UNx-ReninAAV mice were administered (q.d.) vehicle, semaglutide (30 nmol/kg, s.c.) or semaglutide (30 nmol/kg, s.c.) + lisinopril (30 mg/kg, p.o.) for 11 weeks. Endpoints included blood pressure, plasma/urine biochemistry, kidney histopathology and RNA sequencing. Results : Vehicle-dosed db / db UNx-ReninAAV mice developed hallmarks of DKD characterized by severe albuminuria and advanced glomerulosclerosis. Semaglutide robustly reduced hyperglycemia, hypertension and albuminuria concurrent with notable improvements in glomerulosclerosis severity, podocyte filtration slit density, urine/renal kidney injury molecule-1 (KIM-1) levels and gene expression markers of inflammation and fibrogenesis in db / db UNx-ReninAAV mice. Co-administration of lisinopril further ameliorated hypertension and glomerulosclerosis. Conclusions : Semaglutide improves disease hallmarks in the db / db UNx-ReninAAV mouse model of advanced DKD. Further benefits on renal outcomes were obtained by adjunctive antihypertensive standard of care. Collectively, our study supports the development of semaglutide for management of DKD.
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- 2022
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24. Integrative transcriptomic profiling of a mouse model of hypertension-accelerated diabetic kidney disease.
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Sembach FE, Ægidius HM, Fink LN, Secher T, Aarup A, Jelsing J, Vrang N, Feldt-Rasmussen B, Rigbolt KTG, Nielsen JC, and Østergaard MV
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- Animals, Dependovirus metabolism, Disease Models, Animal, Female, Gene Expression Regulation, Kidney Cortex metabolism, Kidney Cortex pathology, Kidney Glomerulus metabolism, Kidney Glomerulus pathology, Mice, Inbred C57BL, Renin metabolism, Mice, Diabetic Nephropathies etiology, Diabetic Nephropathies genetics, Gene Expression Profiling, Hypertension complications
- Abstract
The current understanding of molecular mechanisms driving diabetic kidney disease (DKD) is limited, partly due to the complex structure of the kidney. To identify genes and signalling pathways involved in the progression of DKD, we compared kidney cortical versus glomerular transcriptome profiles in uninephrectomized (UNx) db/db mouse models of early-stage (UNx only) and advanced [UNxplus adeno-associated virus-mediated renin-1 overexpression (UNx-Renin)] DKD using RNAseq. Compared to normoglycemic db/m mice, db/db UNx and db/db UNx-Renin mice showed marked changes in their kidney cortical and glomerular gene expression profiles. UNx-Renin mice displayed more marked perturbations in gene components associated with the activation of the immune system and enhanced extracellular matrix remodelling, supporting histological hallmarks of progressive DKD in this model. Single-nucleus RNAseq enabled the linking of transcriptome profiles to specific kidney cell types. In conclusion, integration of RNAseq at the cortical, glomerular and single-nucleus level provides an enhanced resolution of molecular signalling pathways associated with disease progression in preclinical models of DKD, and may thus be advantageous for identifying novel therapeutic targets in DKD., Competing Interests: Competing interests F.E.S., H.M.Æ., J.C.N., T.S., M.V.Ø., K.T.G.R. and L.N.F. are employees of Gubra ApS. N.V. and J.J. are owners of Gubra ApS., (© 2021. Published by The Company of Biologists Ltd.)
- Published
- 2021
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25. Therapeutic effects of lisinopril and empagliflozin in a mouse model of hypertension-accelerated diabetic kidney disease.
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Østergaard MV, Secher T, Christensen M, Salinas CG, Roostalu U, Skytte JL, Rune I, Hansen HH, Jelsing J, Vrang N, and Fink LN
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- Animals, Antihypertensive Agents pharmacology, Benzhydryl Compounds pharmacology, Diabetic Nephropathies complications, Disease Models, Animal, Female, Glucosides pharmacology, Hypertension complications, Lisinopril pharmacology, Mice, Sodium-Glucose Transporter 2 Inhibitors pharmacology, Treatment Outcome, Antihypertensive Agents therapeutic use, Benzhydryl Compounds therapeutic use, Blood Pressure drug effects, Diabetic Nephropathies drug therapy, Glucosides therapeutic use, Hypertension drug therapy, Lisinopril therapeutic use, Sodium-Glucose Transporter 2 Inhibitors therapeutic use
- Abstract
Hypertension is a critical comorbidity for progression of diabetic kidney disease (DKD). To facilitate the development of novel therapeutic interventions with the potential to control disease progression, there is a need to establish translational animal models that predict treatment effects in human DKD. The present study aimed to characterize renal disease and outcomes of standard of medical care in a model of advanced DKD facilitated by adeno-associated virus (AAV)-mediated renin overexpression in uninephrectomized (UNx) db/db mice. Five weeks after single AAV administration and 4 wk after UNx, female db/db UNx-ReninAAV mice received (PO, QD) vehicle, lisinopril (40 mg/kg), empagliflozin (20 mg/kg), or combination treatment for 12 wk ( n = 17 mice/group). Untreated db /+ mice ( n = 8) and vehicle-dosed db/db UNx-LacZAAV mice ( n = 17) served as controls. End points included plasma, urine, and histomorphometric markers of kidney disease. Total glomerular numbers and individual glomerular volume were evaluated by whole kidney three-dimensional imaging analysis. db/db UNx-ReninAAV mice developed hallmarks of progressive DKD characterized by severe albuminuria, advanced glomerulosclerosis, and glomerular hypertrophy. Lisinopril significantly improved albuminuria, glomerulosclerosis, tubulointerstitial injury, and inflammation. Although empagliflozin alone had no therapeutic effect on renal endpoints, lisinopril and empagliflozin exerted synergistic effects on renal histological outcomes. In conclusion, the db/db UNx-ReninAAV mouse demonstrates good clinical translatability with respect to physiological and histological hallmarks of progressive DKD. The efficacy of standard of care to control hypertension and hyperglycemia provides a proof of concept for testing novel drug therapies in the model. NEW & NOTEWORTHY Translational animal models of diabetic kidney disease (DKD) are important tools in preclinical research and drug discovery. Here, we show that the standard of care to control hypertension (lisinopril) and hyperglycemia (empagliflozin) improves physiological and histopathological hallmarks of kidney disease in a mouse model of hypertension-accelerated progressive DKD. The findings substantiate hypertension and type 2 diabetes as essential factors in driving DKD progression and provide a proof of concept for probing novel drugs for potential nephroprotective efficacy in this model.
- Published
- 2021
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26. Immune Checkpoint and Anti-Angiogenic Antibodies for the Treatment of Non-Small Cell Lung Cancer in the European Union and United States.
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Ferreira M, Secher T, Heuze-Vourc'H N, and Reckamp KL
- Abstract
Several types of antibodies (Abs) are currently used in non-small cell lung cancer (NSCLC). Anti-angiogenic and immune checkpoint inhibitor (ICI) Abs are the most frequent treatments used alone or with chemotherapy in metastatic NSCLC, for the front line and beyond. Considering the many therapeutic options for locally advanced and metastatic lung cancer and differences in use according to geographic area, we present here a comprehensive review of the marketed ICI and anti-angiogenic Abs approved in the European Union (EU) and the US to treat locally advanced and metastatic NSCLC patients. We briefly describe the different molecules and their development in thoracic oncology and compare pharmacokinetic data, processing decision algorithms and marketing authorizations by the EMA and US Food and Drug Administration (FDA).
- Published
- 2021
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27. Chronic Pseudomonas aeruginosa Lung Infection Is IL-1R Independent, but Relies on MyD88 Signaling.
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Mackowiak C, Marchiol T, Paljetak HC, Fauconnier L, Palomo J, Secher T, Panek C, Sedda D, Savigny F, Erard F, Bragonzi A, Huaux F, Stoeger T, Schiller HB, Sirard JC, Le Bert M, Couillin I, Quesniaux VFJ, Togbe D, and Ryffel B
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- Animals, Humans, Immunity, Innate, Interleukin-1beta genetics, Lung immunology, Lung metabolism, Mice, Mice, Inbred C57BL, Mice, Knockout, Myeloid Differentiation Factor 88 genetics, Myeloid Differentiation Factor 88 immunology, Pseudomonas Infections metabolism, Receptors, Interleukin-1 Type I genetics, Signal Transduction, Toll-Like Receptors immunology, Interleukin-1beta immunology, Pseudomonas Infections immunology, Pseudomonas aeruginosa immunology, Receptors, Interleukin-1 Type I immunology
- Abstract
Cystic fibrosis is associated with chronic Pseudomonas aeruginosa colonization and inflammation. The role of MyD88, the shared adapter protein of the proinflammatory TLR and IL-1R families, in chronic P. aeruginosa biofilm lung infection is unknown. We report that chronic lung infection with the clinical P. aeruginosa RP73 strain is associated with uncontrolled lung infection in complete MyD88-deficient mice with epithelial damage, inflammation, and rapid death. Then, we investigated whether alveolar or myeloid cells contribute to heightened sensitivity to infection. Using cell-specific, MyD88-deficient mice, we uncover that the MyD88 pathway in myeloid or alveolar epithelial cells is dispensable, suggesting that other cell types may control the high sensitivity of MyD88-deficient mice. By contrast, IL-1R1-deficient mice control chronic P. aeruginosa RP73 infection and IL-1β Ab blockade did not reduce host resistance. Therefore, the IL-1R1/MyD88 pathway is not involved, but other IL-1R or TLR family members need to be investigated. Our data strongly suggest that IL-1 targeted neutralizing therapies used to treat inflammatory diseases in patients unlikely reduce host resistance to chronic P. aeruginosa infection., (Copyright © 2021 The Authors.)
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- 2021
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28. Rat pancreatectomy combined with isoprenaline or uninephrectomy as models of diabetic cardiomyopathy or nephropathy.
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Thisted L, Østergaard MV, Pedersen AA, Pedersen PJ, Lindsay RT, Murray AJ, Fink LN, Pedersen TX, Secher T, Johansen TT, Thrane ST, Skarsfeldt T, Jelsing J, Thomsen MB, and Zois NE
- Subjects
- Albuminuria complications, Animals, C-Peptide metabolism, Diabetes Mellitus, Experimental metabolism, Disease Models, Animal, Fibrosis, Glomerular Filtration Rate, Heart physiopathology, Isoproterenol pharmacology, Kidney metabolism, Lipocalin-2 metabolism, Male, Rats, Rats, Sprague-Dawley, Renal Insufficiency complications, Diabetic Cardiomyopathies pathology, Diabetic Nephropathies pathology, Pancreatectomy methods
- Abstract
Cardiovascular and renal complications are the predominant causes of morbidity and mortality amongst patients with diabetes. Development of novel treatments have been hampered by the lack of available animal models recapitulating the human disease. We hypothesized that experimental diabetes in rats combined with a cardiac or renal stressor, would mimic diabetic cardiomyopathy and nephropathy, respectively. Diabetes was surgically induced in male Sprague Dawley rats by 90% pancreatectomy (Px). Isoprenaline (Iso, 1 mg/kg, sc., 10 days) was administered 5 weeks after Px with the aim of inducing cardiomyopathy, and cardiac function and remodeling was assessed by echocardiography 10 weeks after surgery. Left ventricular (LV) fibrosis was quantified by Picro Sirius Red and gene expression analysis. Nephropathy was induced by Px combined with uninephrectomy (Px-UNx). Kidney function was assessed by measurement of glomerular filtration rate (GFR) and urine albumin excretion, and kidney injury was evaluated by histopathology and gene expression analysis. Px resulted in stable hyperglycemia, hypoinsulinemia, decreased C-peptide, and increased glycated hemoglobin (HbA1c) compared with sham-operated controls. Moreover, Px increased heart and LV weights and dimensions and caused a shift from α-myosin heavy chain (MHC) to β-MHC gene expression. Isoprenaline treatment, but not Px, decreased ejection fraction and induced LV fibrosis. There was no apparent interaction between Px and Iso treatment. The superimposition of Px and UNx increased GFR, indicating hyperfiltration. Compared with sham-operated controls, Px-UNx induced albuminuria and increased urine markers of kidney injury, including neutrophil gelatinase-associated lipocalin (NGAL) and podocalyxin, concomitant with upregulated renal gene expression of NGAL and kidney injury molecule 1 (KIM-1). Whereas Px and isoprenaline separately produced clinical endpoints related to diabetic cardiomyopathy, the combination of the two did not accentuate disease development. Conversely, Px in combination with UNx resulted in several clinical hallmarks of diabetic nephropathy indicative of early disease development.
- Published
- 2020
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29. MAIT Cells Display a Specific Response to Type 1 IFN Underlying the Adjuvant Effect of TLR7/8 Ligands.
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Pavlovic M, Gross C, Chili C, Secher T, and Treiner E
- Subjects
- Female, Humans, Ligands, Male, Adjuvants, Immunologic pharmacology, Interferon-alpha immunology, Mucosal-Associated Invariant T Cells immunology, Toll-Like Receptor 7 agonists, Toll-Like Receptor 7 immunology, Toll-Like Receptor 8 agonists, Toll-Like Receptor 8 immunology
- Abstract
Mucosal-associated invariant T (MAIT) cells constitute a highly conserved subset of effector T cells with innate-like recognition of a wide array of bacteria and fungi in humans. Harnessing the potential of these cells could represent a major advance as a new immunotherapy approach to fight difficult-to-treat bacterial infections. However, despite recent advances in the design of potent agonistic ligands for MAIT cells, it has become increasingly evident that adjuvants are required to elicit potent antimicrobial effector functions by these cells, such as IFNγ production and cytotoxicity. Indeed, TCR triggering alone elicits mostly barrier repair functions in MAIT cells, whereas an inflammatory milieu is required to drive the antibacterial functions. Cytokines such as IL-7, IL-12 and IL-18, IL-15 or more recently type 1 IFN all display an apparently similar ability to synergize with TCR stimulation to induce IFNγ production and/or cytotoxic functions in vitro , but their mechanisms of action are not well established. Herein, we show that MAIT cells feature a build-in mechanism to respond to IFNα. We confirm that IFNα acts directly and specifically on MAIT cells and synergizes with TCR/CD3 triggering to induce maximum cytokine production and cytotoxic functions. We provide evidences suggesting that the preferential activation of the Stat4 pathway is involved in the high sensitivity of MAIT cells to IFNα stimulation. Finally, gene expression data confirm the specific responsiveness of MAIT cells to IFNα and pinpoints specific pathways that could be the target of this cytokine. Altogether, these data highlight the potential of IFNα-inducing adjuvants to maximize MAIT cells responsiveness to purified ligands in order to induce potent anti-infectious responses., (Copyright © 2020 Pavlovic, Gross, Chili, Secher and Treiner.)
- Published
- 2020
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30. Automated Image Analyses of Glomerular Hypertrophy in a Mouse Model of Diabetic Nephropathy.
- Author
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Østergaard MV, Sembach FE, Skytte JL, Roostalu U, Secher T, Overgaard A, Fink LN, Vrang N, Jelsing J, and Hecksher-Sørensen J
- Subjects
- Animals, Hypertrophy pathology, Kidney pathology, Kidney Glomerulus pathology, Mice, Mice, Inbred Strains, Diabetes Mellitus pathology, Diabetic Nephropathies pathology
- Abstract
Background: Glomerular hypertrophy is a hallmark of kidney injury in metabolically induced renal diseases such as obesity-associated glomerulopathies and diabetic nephropathy (DN)., Methods: Using light sheet fluorescent microscopy (LSFM) and 3D image analysis, we tested algorithms for automated and unbiased quantification of total glomerular numbers and individual glomerular volume in the uninephrectomized (UNx) db/db mouse model of DN., Results: At 6 weeks after surgery, db/db and UNx db/db mice showed increased urine albumin-to-creatinine ratio (ACR) compared with db/+ control mice. Before euthanasia, glomeruli were labeled in vivo by injecting tomato lectin. Whole-kidney LSFM 3D image analysis revealed that mean glomerular volume was significantly increased in UNx db/db mice compared with db/+ mice. Moreover, analysis of individual glomerular volume showed a shift in volume distribution toward larger glomeruli and thereby demonstrated additive effects of diabetes and UNx on induction of glomerular hypertrophy. The automatized quantification showed no significant differences in glomerular numbers among db/+, db/db, and UNx db/db mice. These data correlated with glomerular numbers as quantified by subsequent stereologic quantification., Conclusions: Overall, LSFM coupled with automated 3D histomorphometric analysis was demonstrated to be advantageous for unbiased assessment of glomerular volume and numbers in mouse whole-kidney samples. Furthermore, we showed that injection of fluorescently labeled lectin and albumin can be used as markers of nephron segments in the mouse kidneys, thus enabling functional assessment of kidney physiology, pathology, and pharmacology in preclinical rodent models of kidney disease., Competing Interests: All authors are current employees of Gubra ApS. L. Fink reports other from Novo Nordisk A/S outside the submitted work. J. Jelsing and N. Vrang are owners of Gubra. F. Sembach reports grants from Innovation Foundation outside the submitted work., (Copyright © 2020 by the American Society of Nephrology.)
- Published
- 2020
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31. Impact of sex on diabetic nephropathy and the renal transcriptome in UNx db/db C57BLKS mice.
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Sembach FE, Fink LN, Johansen T, Boland BB, Secher T, Thrane ST, Nielsen JC, Fosgerau K, Vrang N, Jelsing J, Pedersen TX, and Østergaard MV
- Subjects
- Animals, Diabetic Nephropathies metabolism, Diabetic Nephropathies pathology, Female, Kidney metabolism, Kidney pathology, Male, Mice, Mice, Inbred C57BL, Sex Factors, Diabetic Nephropathies genetics, Transcriptome
- Abstract
Diabetic nephropathy (DN) is associated with albuminuria and loss of kidney function and is the leading cause of end-stage renal disease. Despite evidence of sex-associated differences in the progression of DN in human patients, male mice are predominantly being used in preclinical DN research and drug development. Here, we compared renal changes in male and female uninephrectomized (UNx) db/db C57BLKS mice using immunohistochemistry and RNA sequencing. Male and female UNx db/db mice showed similar progression of type 2 diabetes, as assessed by obesity, hyperglycemia, and HbA1c. Progression of DN was also similar between sexes as assessed by kidney and glomerular hypertrophy as well as urine albumin-to-creatinine ratio being increased in UNx db/db compared with control mice. In contrast, kidney collagen III and glomerular collagen IV were increased only in female UNx db/db as compared with respective control mice but showed a similar tendency in male UNx db/db mice. Comparison of renal cortex transcriptomes by RNA sequencing revealed 66 genes differentially expressed (p < .01) in male versus female UNx db/db mice, of which 9 genes were located on the sex chromosomes. In conclusion, male and female UNx db/db mice developed similar hallmarks of DN pathology, suggesting no or weak sex differences in the functional and structural changes during DN progression., (© 2019 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.)
- Published
- 2019
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32. The regenerating family member 3 β instigates IL-17A-mediated neutrophil recruitment downstream of NOD1/2 signalling for controlling colonisation resistance independently of microbiota community structure.
- Author
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Waldschmitt N, Kitamoto S, Secher T, Zacharioudaki V, Boulard O, Floquet E, Delacre M, Lamas B, Pham HP, Six A, Richard ML, Dagorn JC, Eberl G, Langella P, Chatel JM, Ryffel B, Iovanna JL, Poulin LF, Sokol H, Kamada N, and Chamaillard M
- Subjects
- Animals, CARD Signaling Adaptor Proteins physiology, Citrobacter rodentium, Disease Models, Animal, Enterobacteriaceae Infections pathology, Intestinal Mucosa pathology, Mice, Receptor-Interacting Protein Serine-Threonine Kinase 2, Receptor-Interacting Protein Serine-Threonine Kinases physiology, Signal Transduction, Crohn Disease microbiology, Crohn Disease pathology, Enterobacteriaceae Infections prevention & control, Interleukin-17 physiology, Neutrophil Infiltration physiology, Nod2 Signaling Adaptor Protein physiology
- Abstract
Objective: Loss of the Crohn's disease predisposing NOD2 gene results in an intestinal microenvironment conducive for colonisation by attaching-and-effacing enteropathogens. However, it remains elusive whether it relies on the intracellular recruitment of the serine-threonine kinase RIPK2 by NOD2, a step that is required for its activation of the transcription factor NF-κB., Design: Colonisation resistance was evaluated in wild type and mutant mice, as well as in ex-germ-free (ex-GF) mice which were colonised either with faeces from Ripk2 -deficient mice or with bacteria with similar preferences for carbohydrates to those acquired by the pathogen. The severity of the mucosal pathology was quantified at several time points postinfection by using a previously established scoring. The community resilience in response to infection was evaluated by 16S ribosomal RNA gene sequence analysis. The control of pathogen virulence was evaluated by monitoring the secretion of Citrobacter -specific antibody response in the faeces., Results: Primary infection was similarly outcompeted in ex-GF Ripk2 -deficient and control mice, demonstrating that the susceptibility to infection resulting from RIPK2 deficiency cannot be solely attributed to specific microbiota community structures. In contrast, delayed clearance of Citrobacter rodentium and exacerbated histopathology were preceded by a weakened propensity of intestinal macrophages to afford innate lymphoid cell activation. This tissue protection unexpectedly required the regenerating family member 3β by instigating interleukin (IL) 17A-mediated neutrophil recruitment to the intestine and subsequent phosphorylation of signal transducer and activator of transcription 3., Conclusions: These results unveil a previously unrecognised mechanism that efficiently protects from colonisation by diarrhoeagenic bacteria early in infection., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)
- Published
- 2019
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33. The probiotic strain Escherichia coli Nissle 1917 prevents papain-induced respiratory barrier injury and severe allergic inflammation in mice.
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Secher T, Maillet I, Mackowiak C, Le Bérichel J, Philippeau A, Panek C, Boury M, Oswald E, Saoudi A, Erard F, Le Bert M, Quesniaux V, Couturier-Maillard A, and Ryffel B
- Subjects
- Administration, Oral, Animals, Asthma chemically induced, Asthma pathology, Disease Models, Animal, Mice, Mice, Inbred C57BL, Respiratory Mucosa pathology, Th17 Cells immunology, Th2 Cells immunology, Treatment Outcome, Allergens administration & dosage, Asthma prevention & control, Escherichia coli growth & development, Immunologic Factors administration & dosage, Papain administration & dosage, Probiotics administration & dosage
- Abstract
Allergic asthma is characterized by a strong Th2 and Th17 response with inflammatory cell recruitment, airways hyperreactivity and structural changes in the lung. The protease allergen papain disrupts the airway epithelium triggering a rapid eosinophilic inflammation by innate lymphoid cell type 2 (ILC2) activation, leading to a Th2 immune response. Here we asked whether the daily oral administrations of the probiotic Escherichia coli strain Nissle 1917 (ECN) might affect the outcome of the papain protease induced allergic lung inflammation in BL6 mice. We find that ECN gavage significantly prevented the severe allergic response induced by repeated papain challenges and reduced lung inflammatory cell recruitment, Th2 and Th17 response and respiratory epithelial barrier disruption with emphysema and airway hyperreactivity. In conclusion, ECN administration attenuated severe protease induced allergic inflammation, which may be beneficial to prevent allergic asthma.
- Published
- 2018
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34. Oral Administration of the Probiotic Strain Escherichia coli Nissle 1917 Reduces Susceptibility to Neuroinflammation and Repairs Experimental Autoimmune Encephalomyelitis-Induced Intestinal Barrier Dysfunction.
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Secher T, Kassem S, Benamar M, Bernard I, Boury M, Barreau F, Oswald E, and Saoudi A
- Abstract
Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) with an increasing incidence in developed countries. Recent reports suggest that modulation of the gut microbiota might be one promising therapy for MS. Here, we investigated whether the probiotic Escherichia coli strain Nissle 1917 (ECN) could modulate the outcome of experimental autoimmune encephalomyelitis (EAE), a murine model of MS. We evidenced that daily oral treatment with ECN, but not with the archetypal K12 E. coli strain MG1655, reduced the severity of EAE induced by immunization with the MOG
35-55 peptide. This beneficial effect was associated with a decreased secretion of inflammatory cytokines and an increased production of the anti-inflammatory cytokine IL-10 by autoreactive CD4 T cells, both in peripheral lymph nodes and CNS. Interestingly, ECN-treated mice exhibited increased numbers of MOG-specific CD4+ T cells in the periphery contrasting with severely reduced numbers in the CNS, suggesting that ECN might affect T cell migration from the periphery to the CNS through a modulation of their activation and/or differentiation. In addition, we demonstrated that EAE is associated with a profound defect in the intestinal barrier function and that treatment with ECN, but not with MG1655, repaired intestinal permeability dysfunction. Collectively, our data reveal that EAE induces a disruption of the intestinal homeostasis and that ECN protects from disease and restores the intestinal barrier function.- Published
- 2017
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35. Kidney fibroblast growth factor 23 does not contribute to elevation of its circulating levels in uremia.
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Mace ML, Gravesen E, Nordholm A, Hofman-Bang J, Secher T, Olgaard K, and Lewin E
- Subjects
- Animals, Biomarkers blood, Bone and Bones metabolism, Disease Models, Animal, Fibroblast Growth Factors genetics, Fibrosis, Kidney pathology, Kidney physiopathology, Male, Parathyroid Hormone blood, RNA, Messenger genetics, RNA, Messenger metabolism, Rats, Wistar, Receptors, Fibroblast Growth Factor metabolism, Renal Insufficiency, Chronic genetics, Renal Insufficiency, Chronic physiopathology, Time Factors, Up-Regulation, Uremia genetics, Uremia physiopathology, Fibroblast Growth Factors blood, Fibroblasts metabolism, Kidney metabolism, Renal Insufficiency, Chronic blood, Uremia blood
- Abstract
Fibroblast growth factor 23 (FGF23) secreted by osteocytes is a circulating factor essential for phosphate homeostasis. High plasma FGF23 levels are associated with cardiovascular complications and mortality. Increases of plasma FGF23 in uremia antedate high levels of phosphate, suggesting a disrupted feedback regulatory loop or an extra-skeletal source of this phosphatonin. Since induction of FGF23 expression in injured organs has been reported we decided to examine the regulation of FGF23 gene and protein expressions in the kidney and whether kidney-derived FGF23 contributes to the high plasma levels of FGF23 in uremia. FGF23 mRNA was not detected in normal kidneys, but was clearly demonstrated in injured kidneys, already after four hours in obstructive nephropathy and at 8 weeks in the remnant kidney of 5/6 nephrectomized rats. No renal extraction was found in uremic rats in contrast to normal rats. Removal of the remnant kidney had no effect on plasma FGF23 levels. Well-known regulators of FGF23 expression in bone, such as parathyroid hormone, calcitriol, and inhibition of the FGF receptor by PD173074, had no impact on kidney expression of FGF23. Thus, the only direct contribution of the injured kidney to circulating FGF23 levels in uremia appears to be reduced renal extraction of bone-derived FGF23. Kidney-derived FGF23 does not generate high plasma FGF23 levels in uremia and is regulated differently than the corresponding regulation of FGF23 gene expression in bone., (Copyright © 2017 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)
- Published
- 2017
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36. The endogenous preproglucagon system is not essential for gut growth homeostasis in mice.
- Author
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Wismann P, Barkholt P, Secher T, Vrang N, Hansen HB, Jeppesen PB, Baggio LL, Koehler JA, Drucker DJ, Sandoval DA, and Jelsing J
- Subjects
- Animals, Glucagon-Like Peptide-1 Receptor genetics, Glucagon-Like Peptide-2 Receptor genetics, Intestinal Mucosa metabolism, Mice, Mice, Inbred C57BL, Proglucagon genetics, Glucagon-Like Peptide-1 Receptor metabolism, Glucagon-Like Peptide-2 Receptor metabolism, Homeostasis, Intestines growth & development, Proglucagon metabolism
- Abstract
Objective: The prevalence of obesity and related co-morbidities is reaching pandemic proportions. Today, the most effective obesity treatments are glucagon-like peptide 1 (GLP-1) analogs and bariatric surgery. Interestingly, both intervention paradigms have been associated with adaptive growth responses in the gut; however, intestinotrophic mechanisms associated with or secondary to medical or surgical obesity therapies are poorly understood. Therefore, the objective of this study was to assess the local basal endogenous and pharmacological intestinotrophic effects of glucagon-like peptides and bariatric surgery in mice., Methods: We used in situ hybridization to provide a detailed and comparative anatomical map of the local distribution of GLP-1 receptor ( Glp1r ), GLP-2 receptor ( Glp2r ), and preproglucagon ( Gcg ) mRNA expression throughout the mouse gastrointestinal tract. Gut development in GLP-1R-, GLP-2R-, or GCG-deficient mice was compared to their corresponding wild-type controls, and intestinotrophic effects of GLP-1 and GLP-2 analogs were assessed in wild-type mice. Lastly, gut volume was determined in a mouse model of vertical sleeve gastrectomy (VSG)., Results: Comparison of Glp1r , Glp2r , and Gcg mRNA expression indicated a widespread, but distinct, distribution of these three transcripts throughout all compartments of the mouse gastrointestinal tract. While mice null for Glp1r or Gcg showed normal intestinal morphology, Glp2r
-/- mice exhibited a slight reduction in small intestinal mucosa volume. Pharmacological treatment with GLP-1 and GLP-2 analogs significantly increased gut volume. In contrast, VSG surgery had no effect on intestinal morphology., Conclusion: The present study indicates that the endogenous preproglucagon system, exemplified by the entire GCG gene and the receptors for GLP-1 and GLP-2, does not play a major role in normal gut development in the mouse. Furthermore, elevation in local intestinal and circulating levels of GLP-1 and GLP-2 achieved after VSG has limited impact on intestinal morphometry. Hence, although exogenous treatment with GLP-1 and GLP-2 analogs enhances gut growth, the contributions of endogenously-secreted GLP-1 and GLP-2 to gut growth may be more modest and highly context-dependent.- Published
- 2017
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37. Inhibitors of retrograde trafficking active against ricin and Shiga toxins also protect cells from several viruses, Leishmania and Chlamydiales.
- Author
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Gupta N, Noël R, Goudet A, Hinsinger K, Michau A, Pons V, Abdelkafi H, Secher T, Shima A, Shtanko O, Sakurai Y, Cojean S, Pomel S, Liévin-Le Moal V, Leignel V, Herweg JA, Fischer A, Johannes L, Harrison K, Beard PM, Clayette P, Le Grand R, Rayner JO, Rudel T, Vacus J, Loiseau PM, Davey RA, Oswald E, Cintrat JC, Barbier J, and Gillet D
- Subjects
- Animals, Benzamides chemistry, Body Weight drug effects, Chlamydiales drug effects, Ebolavirus drug effects, Escherichia coli metabolism, HEK293 Cells, HeLa Cells, Humans, Injections, Intraperitoneal, Leishmania drug effects, Mice, Mice, Inbred BALB C, Mitomycin pharmacology, Models, Animal, RAW 264.7 Cells, Ricin antagonists & inhibitors, Shiga Toxins antagonists & inhibitors, Thiophenes chemistry, Benzamides pharmacology, Chlamydiales metabolism, Ebolavirus metabolism, Leishmania metabolism, Ricin metabolism, Shiga Toxins metabolism, Thiophenes pharmacology
- Abstract
Medical countermeasures to treat biothreat agent infections require broad-spectrum therapeutics that do not induce agent resistance. A cell-based high-throughput screen (HTS) against ricin toxin combined with hit optimization allowed selection of a family of compounds that meet these requirements. The hit compound Retro-2 and its derivatives have been demonstrated to be safe in vivo in mice even at high doses. Moreover, Retro-2 is an inhibitor of retrograde transport that affects syntaxin-5-dependent toxins and pathogens. As a consequence, it has a broad-spectrum activity that has been demonstrated both in vitro and in vivo against ricin, Shiga toxin-producing O104:H4 entero-hemorrhagic E. coli and Leishmania sp. and in vitro against Ebola, Marburg and poxviruses and Chlamydiales. An effect is anticipated on other toxins or pathogens that use retrograde trafficking and syntaxin-5. Since Retro-2 targets cell components of the host and not directly the pathogen, no selection of resistant pathogens is expected. These lead compounds need now to be developed as drugs for human use., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)
- Published
- 2017
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38. The Food Contaminant Deoxynivalenol Exacerbates the Genotoxicity of Gut Microbiota.
- Author
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Payros D, Dobrindt U, Martin P, Secher T, Bracarense AP, Boury M, Laffitte J, Pinton P, Oswald E, and Oswald IP
- Subjects
- Animals, Coculture Techniques, Epithelial Cells drug effects, Escherichia coli growth & development, Histones analysis, Rats, DNA Damage drug effects, Escherichia coli drug effects, Escherichia coli metabolism, Gastrointestinal Tract microbiology, Mutagens toxicity, Peptides toxicity, Polyketides toxicity, Trichothecenes metabolism
- Abstract
An increasing number of human beings from developed countries are colonized by Escherichia coli strains producing colibactin, a genotoxin suspected to be associated with the development of colorectal cancers. Deoxynivalenol (DON) is the most prevalent mycotoxin that contaminates staple food-especially cereal products-in Europe and North America. This study investigates the effect of the food contaminant DON on the genotoxicity of the E. coli strains producing colibactin. In vitro , intestinal epithelial cells were coexposed to DON and E. coli producing colibactin. In vivo , newborn rats colonized at birth with E. coli producing colibactin were fed a DON-contaminated diet. Intestinal DNA damage was estimated by the phosphorylation of histone H2AX. DON exacerbates the genotoxicity of the E. coli producing colibactin in a time- and dose-dependent manner in vitro Although DON had no effect on the composition of the gut microbiota, and especially on the number of E. coli , a significant increase in DNA damage was observed in intestinal epithelial cells of animals colonized by E. coli strains producing colibactin and coexposed to DON compared to animals colonized with E. coli strains unable to produce colibactin or animals exposed only to DON. In conclusion, our data demonstrate that the genotoxicity of E. coli strains producing colibactin, increasingly present in the microbiota of asymptomatic human beings, is modulated by the presence of DON in the diet. This raises questions about the synergism between food contaminants and gut microbiota with regard to intestinal carcinogenesis. IMPORTANCE An increasing number of human beings from developed countries are colonized by Escherichia coli strains producing colibactin, a genotoxin suspected to be associated with the development of colorectal cancers. Deoxynivalenol (DON) is the most prevalent mycotoxin that contaminates staple food-especially cereal products-in Europe and North America. Our in vitro and in vivo results demonstrate that the intestinal DNA damage induced by colibactin-producing E. coli strains was exacerbated by the presence of DON in the diet. This raises questions about the synergism between food contaminants and gut microbiota with regard to intestinal carcinogenesis., (Copyright © 2017 Payros et al.)
- Published
- 2017
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39. Epithelial IL-23R Signaling Licenses Protective IL-22 Responses in Intestinal Inflammation.
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Aden K, Rehman A, Falk-Paulsen M, Secher T, Kuiper J, Tran F, Pfeuffer S, Sheibani-Tezerji R, Breuer A, Luzius A, Jentzsch M, Häsler R, Billmann-Born S, Will O, Lipinski S, Bharti R, Adolph T, Iovanna JL, Kempster SL, Blumberg RS, Schreiber S, Becher B, Chamaillard M, Kaser A, and Rosenstiel P
- Subjects
- Animals, Colitis chemically induced, Colitis drug therapy, Colitis microbiology, Dextran Sulfate, Dysbiosis drug therapy, Dysbiosis pathology, Epithelial Cells drug effects, Epithelial Cells immunology, Epithelial Cells microbiology, Gene Expression Regulation, Granulocytes drug effects, Granulocytes immunology, Granulocytes microbiology, Interleukin-23 pharmacology, Interleukins genetics, Interleukins pharmacology, Intestinal Mucosa drug effects, Intestinal Mucosa microbiology, Isoantibodies pharmacology, Male, Mice, Mice, Knockout, Neutrophils drug effects, Neutrophils immunology, Neutrophils microbiology, Pancreatitis-Associated Proteins genetics, Pancreatitis-Associated Proteins immunology, Pancreatitis-Associated Proteins pharmacology, Receptors, Interleukin deficiency, Receptors, Interleukin genetics, Signal Transduction, Stem Cells drug effects, Stem Cells immunology, Stem Cells microbiology, Interleukin-22, Colitis immunology, Dysbiosis immunology, Interleukins immunology, Intestinal Mucosa immunology, Receptors, Interleukin immunology
- Abstract
A plethora of functional and genetic studies have suggested a key role for the IL-23 pathway in chronic intestinal inflammation. Currently, pathogenic actions of IL-23 have been ascribed to specific effects on immune cells. Herein, we unveil a protective role of IL-23R signaling. Mice deficient in IL-23R expression in intestinal epithelial cells (Il23R(ΔIEC)) have reduced Reg3b expression, show a disturbed colonic microflora with an expansion of flagellated bacteria, and succumb to DSS colitis. Surprisingly, Il23R(ΔIEC) mice show impaired mucosal IL-22 induction in response to IL-23. αThy-1 treatment significantly deteriorates colitis in Il23R(ΔIEC) animals, which can be rescued by IL-22 application. Importantly, exogenous Reg3b administration rescues DSS-treated Il23R(ΔIEC) mice by recruiting neutrophils as IL-22-producing cells, thereby restoring mucosal IL-22 levels. The study identifies a critical barrier-protective immune pathway that originates from, and is orchestrated by, IL-23R signaling in intestinal epithelial cells., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2016
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40. Early settlers: which E. coli strains do you not want at birth?
- Author
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Secher T, Brehin C, and Oswald E
- Subjects
- Animals, Escherichia coli classification, Escherichia coli metabolism, Host-Pathogen Interactions, Humans, Infant, Newborn, Peptides metabolism, Polyketides metabolism, Symbiosis, Virulence, Escherichia coli pathogenicity, Gastrointestinal Microbiome, Gastrointestinal Tract microbiology
- Abstract
The intestinal microbiota exerts vital biological processes throughout the human lifetime, and imbalances in its composition have been implicated in both health and disease status. Upon birth, the neonatal gut moves from a barely sterile to a massively colonized environment. The development of the intestinal microbiota during the first year of life is characterized by rapid and important changes in microbial composition, diversity, and magnitude. The pioneer bacteria colonizing the postnatal intestinal tract profoundly contribute to the establishment of the host-microbe symbiosis, which is essential for health throughout life. Escherichia coli is one of the first colonizers of the gut after birth. E. coli is a versatile population including harmless commensal, probiotic strains as well as frequently deadly pathogens. The prevalence of the specific phylogenetic B2 group, which encompasses both commensal and extra- or intraintestinal pathogenic E. coli strains, is increasing among E. coli strains colonizing infants quickly after birth. Fifty percent of the B2 group strains carry in their genome the pks gene cluster encoding the synthesis of a nonribosomal peptide-polyketide hybrid genotoxin named colibactin. In this review, we summarize both clinical and experimental evidence associating the recently emerging neonatal B2 E. coli population with several pathology and discuss how the expression of colibactin by both normal inhabitants of intestinal microflora and virulent strains may darken the borderline between commensalism and pathogenicity., (Copyright © 2016 the American Physiological Society.)
- Published
- 2016
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41. DNA Inversion Regulates Outer Membrane Vesicle Production in Bacteroides fragilis.
- Author
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Nakayama-Imaohji H, Hirota K, Yamasaki H, Yoneda S, Nariya H, Suzuki M, Secher T, Miyake Y, Oswald E, Hayashi T, and Kuwahara T
- Subjects
- Anti-Bacterial Agents pharmacology, Bacteroides fragilis drug effects, Bacteroides fragilis physiology, Cell Membrane metabolism, Drug Resistance, Bacterial, Extracellular Vesicles metabolism, Extracellular Vesicles physiology, Gene Expression Regulation, Bacterial genetics, Gene Expression Regulation, Bacterial physiology, Promoter Regions, Genetic genetics, Promoter Regions, Genetic physiology, Proteomics, Sequence Inversion physiology, Bacterial Outer Membrane Proteins biosynthesis, Bacteroides fragilis metabolism, Sequence Inversion genetics
- Abstract
Phase changes in Bacteroides fragilis, a member of the human colonic microbiota, mediate variations in a vast array of cell surface molecules, such as capsular polysaccharides and outer membrane proteins through DNA inversion. The results of the present study show that outer membrane vesicle (OMV) formation in this anaerobe is also controlled by DNA inversions at two distantly localized promoters, IVp-I and IVp-II that are associated with extracellular polysaccharide biosynthesis and the expression of outer membrane proteins. These promoter inversions are mediated by a single tyrosine recombinase encoded by BF2766 (orthologous to tsr19 in strain NCTC9343) in B. fragilis YCH46, which is located near IVp-I. A series of BF2766 mutants were constructed in which the two promoters were locked in different configurations (IVp-I/IVp-II = ON/ON, OFF/OFF, ON/OFF or OFF/ON). ON/ON B. fragilis mutants exhibited hypervesiculating, whereas the other mutants formed only a trace amount of OMVs. The hypervesiculating ON/ON mutants showed higher resistance to treatment with bile, LL-37, and human β-defensin 2. Incubation of wild-type cells with 5% bile increased the population of cells with the ON/ON genotype. These results indicate that B. fragilis regulates the formation of OMVs through DNA inversions at two distantly related promoter regions in response to membrane stress, although the mechanism underlying the interplay between the two regions controlled by the invertible promoters remains unknown.
- Published
- 2016
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42. The anti-diabetic effects of GLP-1-gastrin dual agonist ZP3022 in ZDF rats.
- Author
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Skarbaliene J, Secher T, Jelsing J, Ansarullah, Neerup TS, Billestrup N, and Fosgerau K
- Subjects
- Animals, Blood Glucose, Diabetes Mellitus, Experimental drug therapy, Diabetes Mellitus, Experimental genetics, Diabetes Mellitus, Experimental pathology, Diabetes Mellitus, Type 2 metabolism, Diabetes Mellitus, Type 2 pathology, Gastrins agonists, Glucagon-Like Peptide 1 agonists, Glycated Hemoglobin metabolism, Humans, Insulin metabolism, Insulin-Secreting Cells drug effects, Mice, Rats, Rats, Zucker, Diabetes Mellitus, Type 2 drug therapy, Gastrins metabolism, Glucagon-Like Peptide 1 metabolism, Peptides administration & dosage
- Abstract
Aims/hypothesis: Combination treatment with exendin-4 and gastrin has proven beneficial in treatment of diabetes and preservation of beta cell mass in diabetic mice. Here, we examined the chronic effects of a GLP-1-gastrin dual agonist ZP3022 on glycemic control and beta cell dysfunction in overtly diabetic Zucker Diabetic Fatty (ZDF) rats., Methods: ZDF rats aged 11 weeks were dosed s.c., b.i.d. for 8 weeks with vehicle, ZP3022, liraglutide, exendin-4, or gastrin-17 with or without exendin-4. Glycemic control was assessed by measurements of HbA1c and blood glucose levels, as well as glucose tolerance during an oral glucose tolerance test (OGTT). Beta cell dynamics were examined by morphometric analyses of beta and alpha cell fractions., Results: ZP3022 improved glycemic control as measured by terminal HbA1c levels (6.2±0.12 (high dose) vs. 7.9±0.07% (vehicle), P<0.001), as did all treatments, except gastrin-17 monotherapy. In contrast, only ZP3022, exendin-4 and combination treatment with exendin-4 and gastrin-17 significantly improved glucose tolerance and increased insulin levels during an OGTT. Moreover, only ZP3022 significantly enhanced the beta cell fraction in ZDF rats, a difference of 41%, when compared to the vehicle group (0.31±0.03 vs. 0.22±0.02%, respectively, P<0.05)., Conclusion: These data suggest that ZP3022 may have therapeutic potential in the prevention/delay of beta cell dysfunction in type 2 diabetes., (Copyright © 2015 Elsevier Inc. All rights reserved.)
- Published
- 2015
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43. Neuromedin U inhibits food intake partly by inhibiting gastric emptying.
- Author
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Dalbøge LS, Pedersen SL, Secher T, Holst B, Vrang N, and Jelsing J
- Subjects
- Animals, Diabetes Mellitus metabolism, Diabetes Mellitus pathology, Eating drug effects, Humans, Mice, Neuropeptides administration & dosage, Obesity metabolism, Obesity pathology, Rats, Receptors, Neurotransmitter metabolism, Diabetes Mellitus drug therapy, Gastric Emptying drug effects, Glucose metabolism, Neuropeptides metabolism, Obesity drug therapy
- Abstract
Neuromedin U (NMU) is a gut-brain peptide, implicated in energy and glucose homeostasis via the peripherally expressed NMU receptor 1 (NMUR1) and the central NMUR2. We investigated the effects of a lipidated NMU analog on gastric emptying (GE), glucose homeostasis and food intake to evaluate the use of a NMU analog as drug candidate for treatment of obesity and diabetes. Finally mRNA expression of NMU and NMUR1 in the gut and NMUR2 in the hypothalamus was investigated using a novel chromogen-based in situ hybridization (ISH) assay. Effects on food intake (6 and 18 h post dosing) were addressed in both mice and rats. The effects on GE and glycaemic control were assessed in mice, immediately after the first dose and after seven days of bidaily (BID) dosing. The lipidated NMU analog exerted robust reductions in GE and food intake in mice and improved glycaemic control when measured immediately after the first dose. No effects were observed after seven days BID. In rats, the analog induced only a minor effect on food intake. NMU mRNA was detected in the enteric nervous system throughout the gut, whereas NMUR1 was confined to the lamina propria. NMUR2 was detected in the paraventricular (PVN) and arcuate nuclei (ARC) in mice, with a reduced expression in ARC in rats. In summary, the anorectic effect of the lipidated NMU is partly mediated by a decrease in gastric emptying which is subject to tachyphylaxis after continuous dosing. Susceptibility to NMU appears to be species specific., (Copyright © 2015 Elsevier Inc. All rights reserved.)
- Published
- 2015
- Full Text
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44. Oral tolerance failure upon neonatal gut colonization with Escherichia coli producing the genotoxin colibactin.
- Author
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Secher T, Payros D, Brehin C, Boury M, Watrin C, Gillet M, Bernard-Cadenat I, Menard S, Theodorou V, Saoudi A, Olier M, and Oswald E
- Subjects
- Animals, Animals, Newborn, Carrier State, Female, Pregnancy, Rats, Rats, Wistar, Escherichia coli metabolism, Gastrointestinal Tract microbiology, Peptides metabolism, Polyketides metabolism
- Abstract
The intestinal barrier controls the balance between tolerance and immunity to luminal antigens. When this finely tuned equilibrium is deregulated, inflammatory disorders can occur. There is a concomitant increase, in urban populations of developed countries, of immune-mediated diseases along with a shift in Escherichia coli population from the declining phylogenetic group A to the newly dominant group B2, including commensal strains producing a genotoxin called colibactin that massively colonized the gut of neonates. Here, we showed that mother-to-offspring early gut colonization by colibactin-producing E. coli impairs intestinal permeability and enhances the transepithelial passage of luminal antigen, leading to an increased immune activation. Functionally, this was accompanied by a dramatic increase in local and systemic immune responses against a fed antigen, decreased regulatory T cell population, tolerogenic dendritic cells, and enhanced mucosal delayed-type hypersensitivity response. Conversely, the abolition of colibactin expression by mutagenesis abrogates the alteration of oral tolerance induced by neonatal colonization by E. coli. In conclusion, the vertical colonization by E. coli producing the genotoxin colibactin enhances intestinal translocation and subsequently alters oral tolerance. Thus, early colonization by E. coli from the newly dominant phylogenetic group B2, which produces colibactin, may represent a risk factor for the development of immune-mediated diseases., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)
- Published
- 2015
- Full Text
- View/download PDF
45. Glucagon-like peptide-1 receptor agonists increase pancreatic mass by induction of protein synthesis.
- Author
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Koehler JA, Baggio LL, Cao X, Abdulla T, Campbell JE, Secher T, Jelsing J, Larsen B, and Drucker DJ
- Subjects
- Animals, Antigens, Neoplasm metabolism, Biomarkers, Tumor metabolism, Exenatide, Glucagon-Like Peptide 1 analogs & derivatives, Glucagon-Like Peptide 1 pharmacology, Glucagon-Like Peptide-1 Receptor, Immunohistochemistry, Lectins, C-Type metabolism, Liraglutide, Male, Mice, Mice, Inbred C57BL, Pancreatitis-Associated Proteins, Peptides pharmacology, Protein Biosynthesis drug effects, Proteins metabolism, Venoms pharmacology, Pancreas drug effects, Pancreas metabolism, Receptors, Glucagon agonists, Receptors, Glucagon metabolism
- Abstract
Glucagon-like peptide-1 (GLP-1) controls glucose homeostasis by regulating secretion of insulin and glucagon through a single GLP-1 receptor (GLP-1R). GLP-1R agonists also increase pancreatic weight in some preclinical studies through poorly understood mechanisms. Here we demonstrate that the increase in pancreatic weight following activation of GLP-1R signaling in mice reflects an increase in acinar cell mass, without changes in ductal compartments or β-cell mass. GLP-1R agonists did not increase pancreatic DNA content or the number of Ki67(+) cells in the exocrine compartment; however, pancreatic protein content was increased in mice treated with exendin-4 or liraglutide. The increased pancreatic mass and protein content was independent of cholecystokinin receptors, associated with a rapid increase in S6 phosphorylation, and mediated through the GLP-1R. Rapamycin abrogated the GLP-1R-dependent increase in pancreatic mass but had no effect on the robust induction of Reg3α and Reg3β gene expression. Mass spectrometry analysis identified GLP-1R-dependent upregulation of Reg family members, as well as proteins important for translation and export, including Fam129a, eIF4a1, Wars, and Dmbt1. Hence, pharmacological GLP-1R activation induces protein synthesis, leading to increased pancreatic mass, independent of changes in DNA content or cell proliferation in mice., (© 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)
- Published
- 2015
- Full Text
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46. Blood pressure and glucose independent renoprotective effects of dipeptidyl peptidase-4 inhibition in a mouse model of type-2 diabetic nephropathy.
- Author
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Sharkovska Y, Reichetzeder C, Alter M, Tsuprykov O, Bachmann S, Secher T, Klein T, and Hocher B
- Subjects
- Albuminuria etiology, Albuminuria prevention & control, Angiotensin-Converting Enzyme Inhibitors therapeutic use, Animals, Blood Pressure physiology, Diabetic Nephropathies etiology, Disease Models, Animal, Enalapril therapeutic use, Glucose metabolism, Hypoglycemic Agents pharmacology, Kidney pathology, Kidney Glomerulus pathology, Male, Mice, Mice, Inbred Strains, Renin-Angiotensin System drug effects, Diabetes Mellitus, Type 2 complications, Diabetic Nephropathies prevention & control, Dipeptidyl-Peptidase IV Inhibitors therapeutic use, Linagliptin therapeutic use
- Abstract
Background: Despite the beneficial effects of type 4 dipeptidyl peptidase (DPP-4) inhibitors on glucose levels, its effects on diabetic nephropathy remain unclear., Method: This study examined the long-term renoprotective effects of DPP-4 inhibitor linagliptin in db/db mice, a model of type 2 diabetes. Results were compared with the known beneficial effects of renin-angiotensin system blockade by enalapril. Ten-week-old male diabetic db/db mice were treated for 3 months with either vehicle (n = 10), 3 mg linagliptin/kg per day (n = 8), or 20 mg enalapril/kg per day (n = 10). Heterozygous db/m mice treated with vehicle served as healthy controls (n = 8)., Results: Neither linagliptin nor enalapril had significant effects on the parameters of glucose metabolism or blood pressure in diabetic db/db mice. However, linagliptin treatment reduced albuminuria and attenuated kidney injury. In addition, expression of podocyte marker podocalyxin was normalized. We also analysed DPP-4 expression by immunofluorescence in human kidney biopsies and detected upregulation of DPP-4 in the glomeruli of patients with diabetic nephropathy, suggesting that our findings might be of relevance for human kidney disease as well., Conclusion: Treatment with DPP-4 inhibitor linagliptin delays the progression of diabetic nephropathy damage in a glucose-independent and blood-pressure-independent manner. The observed effects may be because of the attenuation of podocyte injury and inhibition of myofibroblast transformation.
- Published
- 2014
- Full Text
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47. Maternally acquired genotoxic Escherichia coli alters offspring's intestinal homeostasis.
- Author
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Payros D, Secher T, Boury M, Brehin C, Ménard S, Salvador-Cartier C, Cuevas-Ramos G, Watrin C, Marcq I, Nougayrède JP, Dubois D, Bedu A, Garnier F, Clermont O, Denamur E, Plaisancié P, Theodorou V, Fioramonti J, Olier M, and Oswald E
- Subjects
- Animals, Female, Humans, Infant, Newborn, Male, Models, Animal, Pregnancy, Rats, Wistar, DNA Damage drug effects, Escherichia coli metabolism, Gastrointestinal Tract microbiology, Peptides metabolism, Polyketides metabolism
- Abstract
The neonatal gut is rapidly colonized by a newly dominant group of commensal Escherichia coli strains among which a large proportion produces a genotoxin called colibactin. In order to analyze the short- and long-term effects resulting from such evolution, we developed a rat model mimicking the natural transmission of E. coli from mothers to neonates. Genotoxic and non-genotoxic E. coli strains were equally transmitted to the offspring and stably colonized the gut across generations. DNA damage was only detected in neonates colonized with genotoxic E. coli strains. Signs of genotoxic stress such as anaphase bridges, higher occurrence of crypt fission and accelerated renewal of the mature epithelium were detected at adulthood. In addition, we observed alterations of secretory cell populations and gut epithelial barrier. Our findings illustrate how critical is the genotype of E. coli strains acquired at birth for gut homeostasis at adulthood.
- Published
- 2014
- Full Text
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48. Escherichia coli producing colibactin triggers premature and transmissible senescence in mammalian cells.
- Author
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Secher T, Samba-Louaka A, Oswald E, and Nougayrède JP
- Subjects
- Animals, Cell Cycle Checkpoints, Cell Line, DNA Damage, Epithelial Cells microbiology, Epithelial Cells pathology, Escherichia coli Infections genetics, Escherichia coli Infections metabolism, Fibroblasts microbiology, Fibroblasts pathology, Gene Expression Regulation, Humans, Peptides genetics, Rats, beta-Galactosidase genetics, Cellular Senescence, Escherichia coli physiology, Escherichia coli Infections microbiology, Escherichia coli Infections pathology, Host-Pathogen Interactions, Peptides metabolism, Polyketides metabolism
- Abstract
Cellular senescence is an irreversible state of proliferation arrest evoked by a myriad of stresses including oncogene activation, telomere shortening/dysfunction and genotoxic insults. It has been associated with tumor activation, immune suppression and aging, owing to the secretion of proinflammatory mediators. The bacterial genotoxin colibactin, encoded by the pks genomic island is frequently harboured by Escherichia coli strains of the B2 phylogenetic group. Mammalian cells exposed to live pks+ bacteria exhibit DNA-double strand breaks (DSB) and undergo cell-cycle arrest and death. Here we show that cells that survive the acute bacterial infection with pks+ E. coli display hallmarks of cellular senescence: chronic DSB, prolonged cell-cycle arrest, enhanced senescence-associated β-galactosidase (SA-β-Gal) activity, expansion of promyelocytic leukemia nuclear foci and senescence-associated heterochromatin foci. This was accompanied by reactive oxygen species production and pro-inflammatory cytokines, chemokines and proteases secretion. These mediators were able to trigger DSB and enhanced SA-β-Gal activity in bystander recipient cells treated with conditioned medium from senescent cells. Furthermore, these senescent cells promoted the growth of human tumor cells. In conclusion, the present data demonstrated that the E. coli genotoxin colibactin induces cellular senescence and subsequently propel bystander genotoxic and oncogenic effects.
- Published
- 2013
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49. The anti-Pseudomonas aeruginosa antibody Panobacumab is efficacious on acute pneumonia in neutropenic mice and has additive effects with meropenem.
- Author
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Secher T, Fas S, Fauconnier L, Mathieu M, Rutschi O, Ryffel B, and Rudolf M
- Subjects
- Acute Disease, Animals, Anti-Bacterial Agents pharmacology, Anti-Bacterial Agents therapeutic use, Antibodies, Bacterial therapeutic use, Antibodies, Monoclonal therapeutic use, Drug Resistance, Bacterial drug effects, Drug Synergism, Female, Lung drug effects, Lung microbiology, Meropenem, Mice, Mice, Inbred C57BL, Pneumonia complications, Pseudomonas aeruginosa physiology, Thienamycins therapeutic use, Antibodies, Bacterial pharmacology, Antibodies, Monoclonal pharmacology, Neutropenia complications, Pneumonia drug therapy, Pseudomonas aeruginosa drug effects, Pseudomonas aeruginosa immunology, Thienamycins pharmacology
- Abstract
Pseudomonas aeruginosa (P. aeruginosa) infections are associated with considerable morbidity and mortality in immunocompromised patients due to antibiotic resistance. Therefore, we investigated the efficacy of the anti-P. aeruginosa serotype O11 lipopolysaccharide monoclonal antibody Panobacumab in a clinically relevant murine model of neutropenia induced by cyclophosphamide and in combination with meropenem in susceptible and meropenem resistant P. aeruginosa induced pneumonia. We observed that P. aeruginosa induced pneumonia was dramatically increased in neutropenic mice compared to immunocompetent mice. First, Panobacumab significantly reduced lung inflammation and enhanced bacterial clearance from the lung of neutropenic host. Secondly, combination of Panobacumab and meropenem had an additive effect. Third, Panobacumab retained activity on a meropenem resistant P. aeruginosa strain. In conclusion, the present data established that Panobacumab contributes to the clearance of P. aeruginosa in neutropenic hosts as well as in combination with antibiotics in immunocompetent hosts. This suggests beneficial effects of co-treatment even in immunocompromised individuals, suffering most of the morbidity and mortality of P. aeruginosa infections.
- Published
- 2013
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50. NOD2 prevents emergence of disease-predisposing microbiota.
- Author
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Secher T, Normand S, and Chamaillard M
- Subjects
- Animals, Female, Humans, Male, Pregnancy, Colitis etiology, Colorectal Neoplasms etiology, Nod2 Signaling Adaptor Protein deficiency
- Abstract
The gut flora is composed of a huge number of diverse, well-adapted symbionts that interact with epithelial lining throughout the host's entire life. Not all commensals have the same ability to maintain quiescent, protective inflammation. Importantly, instability in the composition of gut microbial communities (referred to as dysbiosis) has been linked to loss of gut barrier in the context of common human illnesses with increasing socio-economic impacts, such as Crohn disease and colorectal cancer. Our recent findings suggest that disease-predisposing dysbiosis can now be intentionally manipulated by targeting the major Crohn disease-predisposing NOD2 gene. That knowledge will not only add a new dimension to the often overlooked microbiology of Crohn disease and colorectal cancer, but will also have a broad impact on biomedical sciences worldwide.
- Published
- 2013
- Full Text
- View/download PDF
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