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Article ; Online: Temporal Regulation of Glomerular and Cortical Tubulointerstitial Genes Involved in the Development of Nephrotoxic Serum Nephritis.

Ougaard, Maria E / Sembach, Frederikke E / Kvist, Peter H / Tonnesen, Morten / Frederiksen, Klaus S / Egfjord, Martin / Jensen, Henrik E / Galsgaard, Elisabeth D

Nephron

2018 Volume 140, Issue 3, Page(s) 218–230

Abstract: Background/aims: Murine nephrotoxic nephritis (NTN) is a well-established model resembling chronic kidney disease. Investigating gene expression patterns separately in the glomerular and cortical tubulointerstitial structure could provide new knowledge ... ...

Abstract	Background/aims: Murine nephrotoxic nephritis (NTN) is a well-established model resembling chronic kidney disease. Investigating gene expression patterns separately in the glomerular and cortical tubulointerstitial structure could provide new knowledge about structure-specific changes in expression of genes in the NTN model. Methods: Glomerular, cortical tubulointerstitial and whole kidney tissues from mice subjected to nephrotoxic serum (NTS) or phosphate buffered saline (PBS) were collected on day 7, 21 and 42 using laser microdissection (LMD). Total RNA was extracted and subjected to nCounter NanoString. Histology, immunohistochemistry, in situ hybridization and/or quantitative real time PCR (qRT PCR) were performed to confirm regulation of selected genes. Results: LMD provided detailed information about genes that were regulated differently between structures over time. Some of the fibrotic and inflammatory genes (Col1a1, Col3a1 and Ccl2) were upregulated in both structures, whereas other genes such as Spp1 and Grem1 were differentially regulated suggesting spatial pathogenic mechanisms in the kidney. Downregulation of cortical tubulointerstitium genes involved in iron metabolism was detected along with iron accumulation. Conclusion: This study demonstrates several regulated genes in pathways important for the pathogenesis of the NTN model and that LMD identifies structure-specific changes in gene expression during disease development. Furthermore, this study shows the benefits of isolating glomeruli and cortical tubulointerstitium in order to identify gene regulation.
MeSH term(s)	Animals ; Female ; Gene Expression Regulation ; Humans ; Inflammation/genetics ; Iron/metabolism ; Kidney Cortex/metabolism ; Kidney Glomerulus/metabolism ; Mice ; Nephritis/blood ; Nephritis/chemically induced ; Nephritis/genetics
Chemical Substances	Iron (E1UOL152H7)
Language	English
Publishing date	2018-09-11
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	207121-6
ISSN	2235-3186 ; 1423-0186 ; 1660-8151 ; 0028-2766
ISSN (online)	2235-3186 ; 1423-0186
ISSN	1660-8151 ; 0028-2766
DOI	10.1159/000492294
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Zs.A 169: Show issues

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Jg. 1995 - 2021: Lesesall (1.OG)
ab Jg. 2022: Lesesaal (EG)

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Article ; Online: NIK/MAP3K14 in hepatocytes orchestrates NASH to hepatocellular carcinoma progression via JAK2/STAT5 inhibition.

Vesting, Anna Juliane / Jais, Alexander / Klemm, Paul / Steuernagel, Lukas / Wienand, Peter / Fog-Tonnesen, Morten / Hvid, Henning / Schumacher, Anna-Lena / Kukat, Christian / Nolte, Hendrik / Georgomanolis, Theodoros / Altmüller, Janine / Pasparakis, Manolis / Schmidt, Andreas / Krüger, Marcus / Supprian, Marc Schmidt / Waisman, Ari / Straub, Beate Katharina / Raschzok, Nathanael /

Bernier, Michel / Birkenfeld, Andreas L / Hövelmeyer, Nadine / Brüning, Jens C / Wunderlich, F Thomas

Molecular metabolism

2022 Volume 66, Page(s) 101626

Abstract: Objective: Nonalcoholic fatty liver disease (NAFLD) ranges from steatosis to nonalcoholic steatohepatitis (NASH), which often progresses to hepatocellular carcinoma (HCC) through a largely undefined mechanism. NASH and HCC depend on inflammatory ... ...

Abstract	Objective: Nonalcoholic fatty liver disease (NAFLD) ranges from steatosis to nonalcoholic steatohepatitis (NASH), which often progresses to hepatocellular carcinoma (HCC) through a largely undefined mechanism. NASH and HCC depend on inflammatory signaling, whose master regulator is the NFκB transcription factor family, activated by canonical and non-canonical pathways. Methods: Here, we investigated non-canonical NFκB-inducing kinase (NIK/MAP3K14) in metabolic NASH, NASH to HCC transition, and DEN-induced HCC. To this end, we performed dietary and chemical interventions in mice that were analyzed via single nucleus sequencing, gene expression and histochemical methods. Ultimately, we verified our mouse results in human patient samples. Results: We revealed that hepatocyte-specific NIK deficiency (NIKLKO) ameliorated metabolic NASH complications and reduced hepatocarcinogenesis, independent of its role in the NFκB pathway. Instead, hepatic NIK attenuated hepatoprotective JAK2/STAT5 signaling that is a prerequisite for NASH and NASH to HCC progression in mice and humans. Conclusions: Our data suggest NIK-mediated inhibitory JAK2 phosphorylation at serine 633 that might be amenable for future therapeutic interventions in patients.
MeSH term(s)	Animals ; Humans ; Mice ; Carcinoma, Hepatocellular/metabolism ; Hepatocytes/metabolism ; Janus Kinase 2/metabolism ; Liver Neoplasms/metabolism ; Non-alcoholic Fatty Liver Disease/metabolism ; STAT5 Transcription Factor/metabolism ; NF-kappaB-Inducing Kinase
Chemical Substances	JAK2 protein, human (EC 2.7.10.2) ; Janus Kinase 2 (EC 2.7.10.2) ; STAT5 Transcription Factor
Language	English
Publishing date	2022-11-07
Publishing country	Germany
Document type	Journal Article
ZDB-ID	2708735-9
ISSN	2212-8778 ; 2212-8778
ISSN (online)	2212-8778
ISSN	2212-8778
DOI	10.1016/j.molmet.2022.101626
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Article ; Online: Macrophage contact dependent and independent TLR4 mechanisms induce β-cell dysfunction and apoptosis in a mouse model of type 2 diabetes.

Cucak, Helena / Mayer, Christopher / Tonnesen, Morten / Thomsen, Lise Høj / Grunnet, Lars Groth / Rosendahl, Alexander

PloS one

2014 Volume 9, Issue 3, Page(s) e90685

Abstract: Type 2 diabetes (T2D) is evolving into a global disease and patients have a systemic low-grade inflammation, yet the role of this inflammation is still not established. One plausible mechanism is enhanced expression and activity of the innate immune ... ...

Abstract	Type 2 diabetes (T2D) is evolving into a global disease and patients have a systemic low-grade inflammation, yet the role of this inflammation is still not established. One plausible mechanism is enhanced expression and activity of the innate immune system. Therefore, we evaluated the expression and the function of the toll-like receptor 4 (TLR4) on pancreatic β-cells in primary mouse islets and on the murine β-cell line MIN6 in the presence or absence of macrophages. Diabetic islets have 40% fewer TLR4 positive β-cells, but twice the number of TLR4 positive macrophages as compared to healthy islets. Healthy and diabetic islets respond to a TLR4 challenge with enhanced production of cytokines (5-10-fold), while the TLR4 negative β-cell line MIN6 fails to produce cytokines. TLR4 stimulation induces β-cell dysfunction in mouse islets, measured as reduced glucose stimulated insulin secretion. Diabetic macrophages from 4-months old mice have acquired a transient enhanced capacity to produce cytokines when stimulated with LPS. Interestingly, this is lost in 6-months old diabetic mice. TLR4 activation alone does not induce apoptosis in islets or MIN-6 cells. In contrast, macrophages mediate TLR4-dependent cell-contact dependent (3-fold) as well as cell-contact independent (2-fold) apoptosis of both islets and MIN-6 cells. Importantly, diabetic macrophages have a significantly enhanced capacity to induce β-cell apoptosis compared to healthy macrophages. Taken together, the TLR4 responsiveness is elevated in the diabetic islets and mainly mediated by newly recruited macrophages. The TLR4 positive macrophages, in both a cell-contact dependent and independent manner, induce apoptosis of β-cells in a TLR4 dependent fashion and TLR4 activation directly induces β-cell dysfunction. Thus, targeting either the TLR4 pathway or the macrophages provides a novel attractive treatment regime for T2D.
MeSH term(s)	Analysis of Variance ; Animals ; Apoptosis/physiology ; Cytokines/metabolism ; Diabetes Mellitus, Type 2/physiopathology ; Female ; Flow Cytometry ; Immunoassay ; Insulin/blood ; Islets of Langerhans/metabolism ; Luminescent Measurements ; Macrophages/metabolism ; Male ; Mice ; Toll-Like Receptor 4/immunology ; Toll-Like Receptor 4/metabolism
Chemical Substances	Cytokines ; Insulin ; Tlr4 protein, mouse ; Toll-Like Receptor 4
Language	English
Publishing date	2014-03-03
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0090685
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Article: Temporal Regulation of Glomerular and Cortical Tubulointerstitial Genes Involved in the Development of Nephrotoxic Serum Nephritis

Ougaard, Maria E. / Sembach, Frederikke E. / Kvist, Peter H. / Tonnesen, Morten / Frederiksen, Klaus S. / Egfjord, Martin / Jensen, Henrik E. / Galsgaard, Elisabeth D.

Nephron

2018 Volume 140, Issue 3, Page(s) 218–230

Abstract: Background/Aims: Murine nephrotoxic nephritis (NTN) is a well-established model resembling chronic kidney disease. Investigating gene expression patterns separately in the glomerular and cortical tubulointerstitial structure could provide new knowledge ... ...

Institution	Novo Nordisk A/S, Måløv, Denmark Department of Veterinary Disease Biology, University of Copenhagen, Copenhagen, Denmark Department of Nephrology, Copenhagen University Hospital, Copenhagen, Denmark
Abstract	Background/Aims: Murine nephrotoxic nephritis (NTN) is a well-established model resembling chronic kidney disease. Investigating gene expression patterns separately in the glomerular and cortical tubulointerstitial structure could provide new knowledge about structure-specific changes in expression of genes in the NTN model. Methods: Glomerular, cortical tubulointerstitial and whole kidney tissues from mice subjected to nephrotoxic serum (NTS) or phosphate buffered saline (PBS) were collected on day 7, 21 and 42 using laser microdissection (LMD). Total RNA was extracted and subjected to nCounter NanoString. Histology, immunohistochemistry, in situ hybridization and/or quantitative real time PCR (qRT PCR) were performed to confirm regulation of selected genes. Results: LMD provided detailed information about genes that were regulated differently between structures over time. Some of the fibrotic and inflammatory genes (Col1a1Col3a1 and Ccl2) were upregulated in both structures, whereas other genes such as Spp1 and Grem1 were differentially regulated suggesting spatial pathogenic mechanisms in the kidney. Downregulation of cortical tubulointerstitium genes involved in iron metabolism was detected along with iron accumulation. Conclusion: This study demonstrates several regulated genes in pathways important for the pathogenesis of the NTN model and that LMD identifies structure-specific changes in gene expression during disease development. Furthermore, this study shows the benefits of isolating glomeruli and cortical tubulointerstitium in order to identify gene regulation.
Keywords	Kidney ; Laser microdissection ; Nephrotoxic nephritis ; Inflammation ; Fibrosis ; Iron
Language	English
Publishing date	2018-09-11
Publisher	S. Karger AG
Publishing place	Basel, Switzerland
Document type	Article
Note	Experimental Nephrology and Genetics: Original Paper
ZDB-ID	207121-6
ISSN	2235-3186 ; 1423-0186 ; 1660-8151 ; 0028-2766
ISSN (online)	2235-3186 ; 1423-0186
ISSN	1660-8151 ; 0028-2766
DOI	10.1159/000492294
Database	Karger publisher's database

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Zs.A 169: Show issues

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Article ; Online: Glucolipotoxic conditions induce β-cell iron import, cytosolic ROS formation and apoptosis.

Hansen, Jakob Bondo / Dos Santos, Laila Romagueira Bichara / Liu, Ying / Prentice, Kacey J / Teudt, Frederik / Tonnesen, Morten / Jonas, Jean-Christophe / Wheeler, Michael B / Mandrup-Poulsen, Thomas

Journal of molecular endocrinology

2018 Volume 61, Issue 2, Page(s) 69–77

Abstract: Type 2 diabetes (T2D) arises when the pancreatic beta-cell fails to compensate for increased insulin needs due to insulin resistance. Glucolipotoxicity (GLT) has been proposed to induce beta-cell dysfunction in T2D by formation of reactive oxygen species ...

Abstract	Type 2 diabetes (T2D) arises when the pancreatic beta-cell fails to compensate for increased insulin needs due to insulin resistance. Glucolipotoxicity (GLT) has been proposed to induce beta-cell dysfunction in T2D by formation of reactive oxygen species (ROS). Here, we examined if modeling glucolipotoxic conditions by high glucose-high free fatty acid (FFA) exposure (GLT) regulates beta-cell iron transport, by increasing the cytosolic labile iron pool (LIP). In isolated mouse islets, the GLT-induced increase in the LIP catalyzed cytosolic ROS formation and induced apoptosis. We show that GLT-induced ROS production is regulated by an increased LIP associated with elevated expression of genes regulating iron import. Using pharmacological and transgenic approaches, we show that iron reduction and decreased iron import protects from GLT-induced ROS production, prevents impairment of the mitochondrial membrane potential (MMP) and inhibits apoptosis. This study identifies a novel pathway underlying GLT-induced apoptosis involving increased iron import, generation of hydroxyl radicals from hydrogen peroxide through the Fenton reaction in the cytosolic compartment associated with dissipation of the MMP and beta-cell apoptosis.
MeSH term(s)	Animals ; Apoptosis/physiology ; Biological Transport/physiology ; Cytosol/metabolism ; Diabetes Mellitus, Type 2/metabolism ; Insulin-Secreting Cells/metabolism ; Iron/metabolism ; Mice ; Reactive Oxygen Species/metabolism
Chemical Substances	Reactive Oxygen Species ; Iron (E1UOL152H7)
Language	English
Publishing date	2018-07-18
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	645012-x
ISSN	1479-6813 ; 0952-5041
ISSN (online)	1479-6813
ISSN	0952-5041
DOI	10.1530/JME-17-0262
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Zs.A 2406: Show issues

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Article ; Online: Disparate phospho-Smad2 levels in advanced type 2 diabetes patients with diabetic nephropathy and early experimental db/db mouse model.

Thomsen, Lise Høj / Fog-Tonnesen, Morten / Nielsen Fink, Lisbeth / Norlin, Jenny / García de Vinuesa, Amaya / Hansen, Troels Krarup / de Heer, Emile / Ten Dijke, Peter / Rosendahl, Alexander

Renal failure

2017 Volume 39, Issue 1, Page(s) 629–642

Abstract: Uncontrolled activation of transforming growth factor beta (TGF-β) family members is hypothesized to participate in type 2 diabetes (T2D) dependent diabetic nephropathy (DN). We evaluated and compared downstream activation of the Smad2-signaling pathway ... ...

Abstract	Uncontrolled activation of transforming growth factor beta (TGF-β) family members is hypothesized to participate in type 2 diabetes (T2D) dependent diabetic nephropathy (DN). We evaluated and compared downstream activation of the Smad2-signaling pathway in kidney samples from T2D patients to kidneys from the T2D model of leptin receptor deficient db/db mouse. Furthermore, expression of TGF-β family members was evaluated to elucidate molecular mechanisms in the mouse model. Kidney samples from patients with advanced stages of DN showed elevated pSmad2 staining whereas db/db mouse kidneys surprisingly showed a decrease in pSmad2 in the tubular compartment. Structurally, kidney tissue showed dilated tubules and expanded glomeruli, but no clear fibrotic pattern was found in the diabetic mice. Selective TGF-β family members were up-regulated at the mRNA level. Antagonists of bone morphogenetic protein (BMP) ligands, such as Gremlin1, USAG1 and Sclerostin, were strongly up-regulated suggesting a dampening effect on BMP pathways. Together, these results indicate a lack of translation from T2D patient kidneys to the db/db model with regards to Smad signaling pathway. It is plausible that a strong up-regulation of BMP antagonizing factors account for the lack of Smad1/5/8 activation, in spite of increased expression of several BMP members.
MeSH term(s)	Adult ; Aged ; Aged, 80 and over ; Animals ; Bone Morphogenetic Proteins/antagonists & inhibitors ; Bone Morphogenetic Proteins/metabolism ; Diabetes Mellitus, Type 2/complications ; Diabetes Mellitus, Type 2/genetics ; Diabetes Mellitus, Type 2/pathology ; Diabetic Nephropathies/etiology ; Diabetic Nephropathies/pathology ; Disease Models, Animal ; Female ; Fibrosis ; Glycoproteins/metabolism ; Humans ; Intercellular Signaling Peptides and Proteins/metabolism ; Kidney Glomerulus/pathology ; Kidney Tubules/pathology ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Obese ; Phosphorylation ; RNA, Messenger/metabolism ; Receptors, Leptin/genetics ; Signal Transduction ; Smad2 Protein/metabolism ; Transforming Growth Factor beta1 ; Up-Regulation
Chemical Substances	Bone Morphogenetic Proteins ; Glycoproteins ; Grem1 protein, mouse ; Intercellular Signaling Peptides and Proteins ; RNA, Messenger ; Receptors, Leptin ; SMAD2 protein, human ; Smad2 Protein ; Smad2 protein, mouse ; Sost protein, mouse ; Sostdc1 protein, mouse ; Transforming Growth Factor beta1 ; leptin receptor, mouse
Language	English
Publishing date	2017-08-14
Publishing country	England
Document type	Journal Article
ZDB-ID	632949-4
ISSN	1525-6049 ; 0886-022X
ISSN (online)	1525-6049
ISSN	0886-022X
DOI	10.1080/0886022X.2017.1361837
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Zs.A 1331: Show issues

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Article ; Online: Smad2 Phosphorylation in Diabetic Kidney Tubule Epithelial Cells Is Associated with Modulation of Several Transforming Growth Factor-β Family Members.

Høj Thomsen, Lise / Fog-Tonnesen, Morten / Nielsen Fink, Lisbeth / Norlin, Jenny / de Vinuesa, Amaya García / Krarup Hansen, Troels / de Heer, Emile / Ten Dijke, Peter / Rosendahl, Alexander

Nephron

2017 Volume 135, Issue 4, Page(s) 291–306

Abstract: Background: The role of transforming growth factor-β (TGF-β) has recently gained much attention in diabetic nephropathy and kidney fibrosis. In this study, we extend this to an assessment of transcriptional regulation of the entire TGF-β superfamily in ... ...

Abstract	Background: The role of transforming growth factor-β (TGF-β) has recently gained much attention in diabetic nephropathy and kidney fibrosis. In this study, we extend this to an assessment of transcriptional regulation of the entire TGF-β superfamily in kidneys from diabetic vs. healthy mice. In order to study the translation between mouse model and patients, we evaluated the signature of phosphorylated Sma- and Mad-related protein 2 (pSmad2), as molecular marker of TGF-β/activin activity, in the kidneys of streptozotocin (STZ)-treated mice compared to that of type 1 diabetes (T1D) patients. Methods: Patterns of pSmad2 were determined in kidneys from T1D patients with progressed diabetic nephropathy (DN), defined by hyperglycemia, microalbuminuria, and increased levels of serum creatinine. They were compared to changes seen in the STZ-induced DN mouse model. This was studied by immunohistochemistry (IHC) with an antibody specific for pSmad2. Diabetic mice were also characterized by pSmad1/5/8 (IHC), pSmad2/3 (flow cytometry), and TGF-β family members including bone morphogenetic protein (BMP)-like proteins (quantitative real-time polymerase chain reaction [qPCR]). Results: Renal tubules in DN patients and in STZ mice showed upregulation of pSmad2 concomitant with significantly enlarged distal tubule lumens (p < 0.0001). Renal-derived CD11b+ cells from STZ mice showed elevated pSmad2/3, while endothelial cells had reduced pSmad2/3 levels. No pSmad1/5/8 was observed in the tubule compartment of STZ-treated mice. On total kidney mRNA level, a signature favoring activation of the TGF-β/activin pathway and inhibition of the BMP pathway was demonstrated by qPCR. Conclusion: Although the pre-clinical DN model lacks the features of fibrosis present in human DN, both species show induction of a local milieu favoring pSmad2 signaling, which may be useful as a disease biomarker in pre-clinical models.
MeSH term(s)	Activins/genetics ; Adult ; Aged ; Aged, 80 and over ; Animals ; Bone Morphogenetic Proteins/genetics ; Diabetes Mellitus, Experimental/genetics ; Diabetes Mellitus, Experimental/metabolism ; Diabetes Mellitus, Experimental/pathology ; Diabetes Mellitus, Type 1/metabolism ; Diabetes Mellitus, Type 1/pathology ; Diabetic Nephropathies/genetics ; Diabetic Nephropathies/metabolism ; Diabetic Nephropathies/pathology ; Epithelial Cells/metabolism ; Epithelial Cells/pathology ; Female ; Humans ; Kidney Tubules/metabolism ; Kidney Tubules/pathology ; Male ; Mice ; Mice, 129 Strain ; Middle Aged ; Models, Biological ; Phosphorylation ; Smad2 Protein/blood ; Smad2 Protein/metabolism ; Smad3 Protein/blood ; Transforming Growth Factor beta/genetics ; Transforming Growth Factor beta/metabolism ; Up-Regulation
Chemical Substances	Bone Morphogenetic Proteins ; SMAD2 protein, human ; Smad2 Protein ; Smad2 protein, mouse ; Smad3 Protein ; Smad3 protein, mouse ; Transforming Growth Factor beta ; activin A ; Activins (104625-48-1)
Language	English
Publishing date	2017
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	207121-6
ISSN	2235-3186 ; 1423-0186 ; 1660-8151 ; 0028-2766
ISSN (online)	2235-3186 ; 1423-0186
ISSN	1660-8151 ; 0028-2766
DOI	10.1159/000453337
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Zs.A 169: Show issues

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Article ; Online: Regulation of the β-cell inflammasome and contribution to stress-induced cellular dysfunction and apoptosis.

Ghiasi, Seyed Mojtaba / Dahllöf, Mattias Salling / Osmai, Yama / Osmai, Mirwais / Jakobsen, Kathrine Kronberg / Aivazidis, Alexander / Tyrberg, Björn / Perruzza, Lisa / Prause, Michala Cecilie Burstein / Christensen, Dan Ploug / Fog-Tonnesen, Morten / Lundh, Morten / Grassi, Fabio / Chatenoud, Lucienne / Mandrup-Poulsen, Thomas

Molecular and cellular endocrinology

2018 Volume 478, Page(s) 106–114

Abstract: β-Cells may be a source of IL-1β that is produced as inactive pro-IL-1β and processed into biologically-active IL-1β by enzymatic cleavage mediated by the NLRP1-, NLRP3- and NLRC4-inflammasomes. Little is known about the β-cell inflammasomes. NLRP1- ... ...

Abstract	β-Cells may be a source of IL-1β that is produced as inactive pro-IL-1β and processed into biologically-active IL-1β by enzymatic cleavage mediated by the NLRP1-, NLRP3- and NLRC4-inflammasomes. Little is known about the β-cell inflammasomes. NLRP1-expression was upregulated in islet-cells from T2D-patients and by IL-1β+IFNγ in INS-1 cells in a histone-deacetylase dependent manner. NLRP3 was downregulated by cytokines in INS-1 cells. NLRC4 was barely expressed and not regulated by cytokines. High extracellular K
MeSH term(s)	Animals ; Apoptosis/drug effects ; CARD Signaling Adaptor Proteins ; Cell Death/drug effects ; Cell Line ; Cytokines/pharmacology ; Cytoprotection/drug effects ; Female ; Glucose/toxicity ; Histone Deacetylases/metabolism ; Humans ; Inflammasomes/metabolism ; Insulin Secretion/drug effects ; Insulin-Secreting Cells/drug effects ; Insulin-Secreting Cells/metabolism ; Interleukin-1beta/metabolism ; JNK Mitogen-Activated Protein Kinases/metabolism ; Lipids/toxicity ; Middle Aged ; Potassium/pharmacology ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; Rats ; Receptors, Purinergic P2X7/metabolism ; Stress, Physiological/drug effects ; Young Adult
Chemical Substances	CARD Signaling Adaptor Proteins ; Cytokines ; Inflammasomes ; Interleukin-1beta ; Lipids ; P2rx7 protein, rat ; Pycard protein, rat ; RNA, Messenger ; Receptors, Purinergic P2X7 ; JNK Mitogen-Activated Protein Kinases (EC 2.7.11.24) ; Histone Deacetylases (EC 3.5.1.98) ; Glucose (IY9XDZ35W2) ; Potassium (RWP5GA015D)
Language	English
Publishing date	2018-08-16
Publishing country	Ireland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	187438-x
ISSN	1872-8057 ; 0303-7207
ISSN (online)	1872-8057
ISSN	0303-7207
DOI	10.1016/j.mce.2018.08.001
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Zs.A 1127: Show issues

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Article ; Online: Inhibition of the nuclear factor-κB pathway prevents beta cell failure and diet induced diabetes in Psammomys obesus.

Friberg, Josefine / Tonnesen, Morten F / Heller, Schott / Pociot, Flemming / Bödvarsdottir, Thóra B / Karlsen, Allan E

PloS one

2010 Volume 5, Issue 10, Page(s) e13341

Abstract: Background: High doses of anti-inflammatory drugs, such as aspirin and salicylates, improve glucose metabolism in insulin resistant and type 2 diabetic patients. It has also been shown that the glucose lowering effect is related to the unspecific ... ...

Abstract	Background: High doses of anti-inflammatory drugs, such as aspirin and salicylates, improve glucose metabolism in insulin resistant and type 2 diabetic patients. It has also been shown that the glucose lowering effect is related to the unspecific ability of these drugs to inhibit inhibitor kinaseβ (IKKβ). In this study we have investigated the effect of a selective IKKβ-inhibitor on beta cell survival and the prevention of diet induced type 2 diabetes in the gerbil Psammomys obesus (P. obesus). Methodology/principal findings: P. obesus were fed a diabetes inducing high energy diet for one month in the absence or presence of the IKKβ-inhibitor. Body mass, blood glucose, HbA(1C), insulin production and pancreatic insulin stores were measured. The effects on beta cell survival were also studied in INS-1 cells and primary islets. The cells were exposed to IL-1β and subsequently reactive oxygen species, insulin release and cell death were measured in the absence or presence of the IKKβ-inhibitor. In primary islets and beta cells, IL-1β induced the production of reactive oxygen species, reduced insulin production and increased beta cell death, which were all reversed by pre-treatment with the IKKβ-inhibitor. In P. obesus the IKKβ-inhibitor prevented the development of hyperglycaemia and hyperinsulinaemia, and maintained pancreatic insulin stores with no effect on body weight. Conclusions/significance: Inhibition of IKKβ activity prevents diet-induced diabetes in P. obesus and inhibits IL-1β induced reactive oxygen species, loss of insulin production and beta cell death in vitro.
MeSH term(s)	Animals ; Cells, Cultured ; Diabetes Mellitus, Experimental/metabolism ; Diabetes Mellitus, Experimental/physiopathology ; Diet ; Gerbillinae ; I-kappa B Kinase/antagonists & inhibitors ; Interleukin-1beta/pharmacology ; Islets of Langerhans/metabolism ; Islets of Langerhans/physiopathology ; NF-kappa B/antagonists & inhibitors ; NF-kappa B/metabolism ; Rats
Chemical Substances	Interleukin-1beta ; NF-kappa B ; I-kappa B Kinase (EC 2.7.11.10)
Language	English
Publishing date	2010-10-11
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0013341
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: RNA modifications by oxidation: A novel disease mechanism?

Poulsen, Henrik E / Specht, Elisabeth / Broedbaek, Kasper / Henriksen, Trine / Ellervik, Christina / Mandrup-Poulsen, Thomas / Tonnesen, Morten / Nielsen, Peter E / Andersen, Henrik U / Weimann, Allan

Free Radical Biology and Medicine. 2012 Apr. 15, v. 52, no. 8

2012

Abstract: The past decade has provided exciting insights into a novel class of central (small) RNA molecules intimately involved in gene regulation. Only a small percentage of our DNA is translated into proteins by mRNA, yet 80% or more of the DNA is transcribed ... ...

Abstract	The past decade has provided exciting insights into a novel class of central (small) RNA molecules intimately involved in gene regulation. Only a small percentage of our DNA is translated into proteins by mRNA, yet 80% or more of the DNA is transcribed into RNA, and this RNA has been found to encompass various classes of novel regulatory RNAs, including, e.g., microRNAs. It is well known that DNA is constantly oxidized and repaired by complex genome maintenance mechanisms. Analogously, RNA also undergoes significant oxidation, and there are now convincing data suggesting that oxidation, and the consequent loss of integrity of RNA, is a mechanism for disease development. Oxidized RNA is found in a large variety of diseases, and interest has been especially devoted to degenerative brain diseases such as Alzheimer disease, in which up to 50–70% of specific mRNA molecules are reported oxidized, whereas other RNA molecules show virtually no oxidation. The iron-storage disease hemochromatosis exhibits the most prominent general increase in RNA oxidation ever observed. Oxidation of RNA primarily leads to strand breaks and to oxidative base modifications. Oxidized mRNA is recognized by the ribosomes, but the oxidation results in ribosomal stalling and dysfunction, followed by decreased levels of functional protein as well as the production of truncated proteins that do not undergo proper folding and may result in protein aggregation within the cell. Ribosomal dysfunction may also signal apoptosis by p53-independent pathways. There are very few reports on interventions that reduce RNA oxidation, one interesting observation being a reduction in RNA oxidation by ingestion of raw olive oil. High urinary excretion of 8-oxo-guanosine, a biomarker for RNA oxidation, is highly predictive of death in newly diagnosed type 2 diabetics; this demonstrates the clinical relevance of RNA oxidation. Taken collectively the available data suggest that RNA oxidation is a contributing factor in several diseases such as diabetes, hemochromatosis, heart failure, and β-cell destruction. The mechanism involves free iron and hydrogen peroxide from mitochondrial dysfunction that together lead to RNA oxidation that in turn gives rise to truncated proteins that may cause aggregation. Thus RNA oxidation may well be an important novel contributing mechanism for several diseases.
Keywords	Alzheimer disease ; DNA ; apoptosis ; biomarkers ; death ; diabetes ; excretion ; genes ; heart failure ; hemochromatosis ; hydrogen peroxide ; ingestion ; iron ; messenger RNA ; microRNA ; olive oil ; oxidation ; proteins ; ribosomes ; translation (genetics)
Language	English
Dates of publication	2012-0415
Size	p. 1353-1361.
Publishing place	Elsevier Inc.
Document type	Article
ZDB-ID	807032-5
ISSN	1873-4596 ; 0891-5849
ISSN (online)	1873-4596
ISSN	0891-5849
DOI	10.1016/j.freeradbiomed.2012.01.009
Database	NAL-Catalogue (AGRICOLA)

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