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Article ; Online: Genomic targets of the IRE1-XBP1s pathway in mediating metabolic adaptation in epithelial plasticity.

Qiao, Dianhua / Skibba, Melissa / Xu, Xiaofang / Brasier, Allan R

2023 Volume 51, Issue 8, Page(s) 3650–3670

Abstract: Epithelial mesenchymal plasticity (EMP) is a complex cellular reprogramming event that plays a major role in tissue homeostasis. Recently we observed the unfolded protein response (UPR) triggers EMP through the inositol-requiring protein 1 (IRE1α)-X-box- ... ...

Abstract	Epithelial mesenchymal plasticity (EMP) is a complex cellular reprogramming event that plays a major role in tissue homeostasis. Recently we observed the unfolded protein response (UPR) triggers EMP through the inositol-requiring protein 1 (IRE1α)-X-box-binding protein 1 spliced (XBP1s) axis, enhancing glucose shunting to protein N glycosylation. To better understand the genomic targets of XBP1s, we identified its genomic targets using Cleavage Under Targets and Release Using Nuclease (CUT&RUN) of a FLAG-epitope tagged XBP1s in RSV infection. CUT&RUN identified 7086 binding sites in chromatin that were enriched in AP-1 motifs and GC-sequences. Of these binding sites, XBP1s peaks mapped to 4827 genes controlling Rho-GTPase signaling, N-linked glycosylation and ER-Golgi transport. Strikingly, XBP1s peaks were within 1 kb of transcription start sites of 2119 promoters. In addition to binding core mesenchymal transcription factors SNAI1 and ZEB1, we observed that hexosamine biosynthetic pathway (HBP) enzymes were induced and contained proximal XBP1s peaks. We demonstrate that IRE1α -XBP1s signaling is necessary and sufficient to activate core enzymes by recruiting elongation-competent phospho-Ser2 CTD modified RNA Pol II. We conclude that the IRE1α-XBP1s pathway coordinately regulates mesenchymal transcription factors and hexosamine biosynthesis in EMP by a mechanism involving recruitment of activated pSer2-Pol II to GC-rich promoters.
MeSH term(s)	Endoplasmic Reticulum Stress ; Endoribonucleases/metabolism ; Genomics ; Hexosamines ; Protein Serine-Threonine Kinases/genetics ; Protein Serine-Threonine Kinases/metabolism ; Transcription Factors/genetics ; Transcription Factors/metabolism ; Unfolded Protein Response ; Epithelium/physiology ; Respiratory System/cytology ; Humans
Chemical Substances	Endoribonucleases (EC 3.1.-) ; Hexosamines ; Protein Serine-Threonine Kinases (EC 2.7.11.1) ; Transcription Factors
Language	English
Publishing date	2023-03-06
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	186809-3
ISSN	1362-4962 ; 1362-4954 ; 0301-5610 ; 0305-1048
ISSN (online)	1362-4962 ; 1362-4954
ISSN	0301-5610 ; 0305-1048
DOI	10.1093/nar/gkad077
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Article ; Online: The IRE1α-XBP1s Arm of the Unfolded Protein Response Activates N-Glycosylation to Remodel the Subepithelial Basement Membrane in Paramyxovirus Infection.

Zhao, Yingxin / Qiao, Dianhua / Skibba, Melissa / Brasier, Allan R

International journal of molecular sciences

2022 Volume 23, Issue 16

Abstract: Respiratory syncytial virus (RSV) causes severe lower respiratory tract infections (LRTI) associated with decreased pulmonary function, asthma, and allergy. Recently, we demonstrated that RSV induces the hexosamine biosynthetic pathway via the unfolded ... ...

Abstract	Respiratory syncytial virus (RSV) causes severe lower respiratory tract infections (LRTI) associated with decreased pulmonary function, asthma, and allergy. Recently, we demonstrated that RSV induces the hexosamine biosynthetic pathway via the unfolded protein response (UPR), which is a pathway controlling protein glycosylation and secretion of the extracellular matrix (ECM). Because the presence of matrix metalloproteinases and matricellular growth factors (TGF) is associated with severe LRTI, we studied the effect of RSV on ECM remodeling and found that RSV enhances the deposition of fibronectin-rich ECM by small airway epithelial cells in a manner highly dependent on the inositol requiring kinase (IRE1α)-XBP1 arm of the UPR. To understand this effect comprehensively, we applied pharmacoproteomics to understand the effect of the UPR on N-glycosylation and ECM secretion in RSV infection. We observe that RSV induces N-glycosylation and the secretion of proteins related to ECM organization, secretion, or proteins integral to plasma membranes, such as integrins, laminins, collagens, and ECM-modifying enzymes, in an IRE1α-XBP1 dependent manner. Using a murine paramyxovirus model that activates the UPR in vivo, we validate the IRE1α-XBP1-dependent secretion of ECM to alveolar space. This study extends understanding of the IRE1α-XBP1 pathway in regulating N-glycosylation coupled to structural remodeling of the epithelial basement membrane in RSV infection.
MeSH term(s)	Animals ; Basement Membrane/metabolism ; Endoribonucleases/metabolism ; Glycosylation ; Mice ; Protein Serine-Threonine Kinases ; Respiratory Syncytial Virus Infections/metabolism ; Signal Transduction ; Unfolded Protein Response ; X-Box Binding Protein 1/metabolism
Chemical Substances	X-Box Binding Protein 1 ; Xbp1 protein, mouse ; Ern1 protein, mouse (EC 2.7.11.1) ; Protein Serine-Threonine Kinases (EC 2.7.11.1) ; Endoribonucleases (EC 3.1.-)
Language	English
Publishing date	2022-08-12
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms23169000
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Article ; Online: Selective Inhibition of Bromodomain-Containing Protein 4 Reduces Myofibroblast Transdifferentiation and Pulmonary Fibrosis.

Bernau, Ksenija / Skibba, Melissa / Leet, Jonathan P / Furey, Sierra / Gehl, Carson / Li, Yi / Zhou, Jia / Sandbo, Nathan / Brasier, Allan R

Frontiers in molecular medicine

2022 Volume 2

Abstract: Idiopathic pulmonary fibrosis is a lethal disease driven by myofibroblast expansion. Currently no therapies exist that target the epigenetic mechanisms controlling myofibroblast transdifferentiation, which is responsible for unregulated extracellular ... ...

Abstract	Idiopathic pulmonary fibrosis is a lethal disease driven by myofibroblast expansion. Currently no therapies exist that target the epigenetic mechanisms controlling myofibroblast transdifferentiation, which is responsible for unregulated extracellular matrix (ECM) production. We have recently shown that bromodomain-containing protein 4 (BRD4), an epigenetic regulator that forms a scaffold for nuclear activators and transcription factors, is essential for TGFβ-induced myofibroblast transdifferentiation. However, its role in the development and progression of pulmonary fibrosis
Language	English
Publishing date	2022-03-15
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	3123823-3
ISSN	2674-0095 ; 2674-0095
ISSN (online)	2674-0095
ISSN	2674-0095
DOI	10.3389/fmmed.2022.842558
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Article ; Online: Paramyxovirus replication induces the hexosamine biosynthetic pathway and mesenchymal transition via the IRE1α-XBP1s arm of the unfolded protein response.

Qiao, Dianhua / Skibba, Melissa / Xu, Xiaofang / Garofalo, Roberto P / Zhao, Yingxin / Brasier, Allan R

American journal of physiology. Lung cellular and molecular physiology

2021 Volume 321, Issue 3, Page(s) L576–L594

Abstract: The paramyxoviridae, respiratory syncytial virus (RSV), and murine respirovirus are enveloped, negative-sense RNA viruses that are the etiological agents of vertebrate lower respiratory tract infections (LRTIs). We observed that RSV infection in human ... ...

Abstract	The paramyxoviridae, respiratory syncytial virus (RSV), and murine respirovirus are enveloped, negative-sense RNA viruses that are the etiological agents of vertebrate lower respiratory tract infections (LRTIs). We observed that RSV infection in human small airway epithelial cells induced accumulation of glycosylated proteins within the endoplasmic reticulum (ER), increased glutamine-fructose-6-phosphate transaminases (GFPT1/2) and accumulation of uridine diphosphate (UDP)-
MeSH term(s)	Animals ; Cell Line, Transformed ; Endoribonucleases/genetics ; Endoribonucleases/metabolism ; Epithelial Cells/metabolism ; Epithelial Cells/pathology ; Epithelial Cells/virology ; Extracellular Matrix/genetics ; Extracellular Matrix/metabolism ; Extracellular Matrix/pathology ; Hexosamines/biosynthesis ; Hexosamines/genetics ; Humans ; Mice ; Protein Serine-Threonine Kinases/genetics ; Protein Serine-Threonine Kinases/metabolism ; Respiratory Mucosa/metabolism ; Respiratory Mucosa/pathology ; Respiratory Mucosa/virology ; Respiratory Syncytial Virus Infections/genetics ; Respiratory Syncytial Virus Infections/metabolism ; Respiratory Syncytial Virus Infections/pathology ; Respiratory Syncytial Virus, Human/physiology ; Unfolded Protein Response ; Virus Replication ; X-Box Binding Protein 1/genetics ; X-Box Binding Protein 1/metabolism
Chemical Substances	Hexosamines ; X-Box Binding Protein 1 ; XBP1 protein, human ; Xbp1 protein, mouse ; ERN1 protein, human (EC 2.7.11.1) ; Ern1 protein, mouse (EC 2.7.11.1) ; Protein Serine-Threonine Kinases (EC 2.7.11.1) ; Endoribonucleases (EC 3.1.-)
Language	English
Publishing date	2021-07-28
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1013184-x
ISSN	1522-1504 ; 1040-0605
ISSN (online)	1522-1504
ISSN	1040-0605
DOI	10.1152/ajplung.00127.2021
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Zs.A 2749: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)

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Article ; Online: Role of Secretoglobin

Skibba, Melissa E / Xu, Xiaofang / Weiss, Kurt / Huisken, Jan / Brasier, Allan R

Respiratory research

2021 Volume 22, Issue 1, Page(s) 315

Abstract: Repetitive aeroallergen exposure is linked to sensitization and airway remodeling through incompletely understood mechanisms. In this study, we examine the dynamic mucosal response to cat dander extract (CDE), a ubiquitous aero-allergen linked to ... ...

Abstract	Repetitive aeroallergen exposure is linked to sensitization and airway remodeling through incompletely understood mechanisms. In this study, we examine the dynamic mucosal response to cat dander extract (CDE), a ubiquitous aero-allergen linked to remodeling, sensitization and asthma. We find that daily exposure of CDE in naïve C57BL/6 mice activates innate neutrophilic inflammation followed by transition to a lymphocytic response associated with waves of mucosal transforming growth factor (TGF) isoform expression. In parallel, enhanced bronchiolar Smad3 expression and accumulation of phospho-SMAD3 was observed, indicating paracrine activation of canonical TGFβR signaling. CDE exposure similarly triggered epithelial cell plasticity, associated with expression of mesenchymal regulatory factors (Snai1 and Zeb1), reduction of epithelial markers (Cdh1) and activation of the NFκB/RelA transcriptional activator. To determine whether NFκB functionally mediates CDE-induced growth factor response, mice were stimulated with CDE in the absence or presence of a selective IKK inhibitor. IKK inhibition substantially reduced the level of CDE-induced TGFβ1 expression, pSMAD3 accumulation, Snai1 and Zeb1 expression. Activation of epithelial plasticity was demonstrated by flow cytometry in whole lung homogenates, where CDE induces accumulation of SMA
MeSH term(s)	Airway Remodeling ; Allergens/adverse effects ; Animals ; Asthma/genetics ; Asthma/metabolism ; Asthma/pathology ; Bronchioles/metabolism ; Bronchioles/pathology ; Cats ; Cell Transdifferentiation ; Cells, Cultured ; Disease Models, Animal ; Gene Expression Regulation ; Humans ; Mice ; Mice, Inbred C57BL ; Myofibroblasts/metabolism ; Myofibroblasts/pathology ; NF-kappa B/biosynthesis ; NF-kappa B/genetics ; Secretoglobins/metabolism ; Signal Transduction ; Transforming Growth Factor beta/biosynthesis ; Transforming Growth Factor beta/genetics
Chemical Substances	Allergens ; NF-kappa B ; Secretoglobins ; Transforming Growth Factor beta
Language	English
Publishing date	2021-12-20
Publishing country	England
Document type	Journal Article
ZDB-ID	2041675-1
ISSN	1465-993X ; 1465-993X
ISSN (online)	1465-993X
ISSN	1465-993X
DOI	10.1186/s12931-021-01910-w
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Article: Nanoapproaches to Modifying Epigenetics of Epithelial Mesenchymal Transition for Treatment of Pulmonary Fibrosis.

Skibba, Melissa / Drelich, Adam / Poellmann, Michael / Hong, Seungpyo / Brasier, Allan R

Frontiers in pharmacology

2020 Volume 11, Page(s) 607689

Abstract: Idiopathic Pulmonary Fibrosis (IPF) is a chronically progressive interstitial lung that affects over 3 M people worldwide and rising in incidence. With a median survival of 2-3 years, IPF is consequently associated with high morbidity, mortality, and ... ...

Abstract	Idiopathic Pulmonary Fibrosis (IPF) is a chronically progressive interstitial lung that affects over 3 M people worldwide and rising in incidence. With a median survival of 2-3 years, IPF is consequently associated with high morbidity, mortality, and healthcare burden. Although two antifibrotic therapies, pirfenidone and nintedanib, are approved for human use, these agents reduce the rate of decline of pulmonary function but are not curative and do not reverse established fibrosis. In this review, we discuss the prevailing epithelial injury hypothesis, wherein pathogenic airway epithelial cell-state changes known as Epithelial Mesenchymal Transition (EMT) promotes the expansion of myofibroblast populations. Myofibroblasts are principal components of extracellular matrix production that result in airspace loss and mortality. We review the epigenetic transition driving EMT, a process produced by changes in histone acetylation regulating mesenchymal gene expression programs. This mechanistic work has focused on the central role of bromodomain-containing protein 4 in mediating EMT and myofibroblast transition and initial preclinical work has provided evidence of efficacy. As nanomedicine presents a promising approach to enhancing the efficacy of such anti-IPF agents, we then focus on the state of nanomedicine formulations for inhalable delivery in the treatment of pulmonary diseases, including liposomes, polymeric nanoparticles (NPs), inorganic NPs, and exosomes. These nanoscale agents potentially provide unique properties to existing pulmonary therapeutics, including controlled release, reduced systemic toxicity, and combination delivery. NP-based approaches for pulmonary delivery thus offer substantial promise to modify epigenetic regulators of EMT and advance treatments for IPF.
Language	English
Publishing date	2020-12-11
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2587355-6
ISSN	1663-9812
ISSN	1663-9812
DOI	10.3389/fphar.2020.607689
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Article ; Online: iRGD decorated lipid-polymer hybrid nanoparticles for targeted co-delivery of doxorubicin and sorafenib to enhance anti-hepatocellular carcinoma efficacy.

Zhang, Jinming / Hu, Jie / Chan, Hon Fai / Skibba, Melissa / Liang, Guang / Chen, Meiwan

Nanomedicine : nanotechnology, biology, and medicine

2016 Volume 12, Issue 5, Page(s) 1303–1311

Abstract: The combination of doxorubicin (DOX) with sorafenib (SOR) has proven an effective strategy to enhance anti-hepatocellular carcinoma (HCC) efficacy. However, respective in vivo pharmacokinetic profiles and different endocytosis capacities of these two ... ...

Abstract	The combination of doxorubicin (DOX) with sorafenib (SOR) has proven an effective strategy to enhance anti-hepatocellular carcinoma (HCC) efficacy. However, respective in vivo pharmacokinetic profiles and different endocytosis capacities of these two drugs greatly hinder their current application. Herein, the tumor-targeting peptide iRGD decorated lipid-polymer hybrid nanoparticles (NPs) with a shell-core structure were developed for co-delivery of DOX and SOR (DOX+SOR/iRGD NPs). After the drug ratio was optimized, the stabilized DOX+SOR/iRGD NPs were prepared. Through the iRGD-integrin recognition, DOX+SOR/iRGD NPs showed synergistic cytotoxicity, pro-apoptotic ability and enhanced internalization rate in human liver cancer HepG2 cells. In vivo pharmacokinetic result demonstrated that an extended circulation and bioavailability of DOX+SOR/iRGD NPs than free drugs. More importantly, DOX+SOR/iRGD NPs significantly enhanced antitumor efficiency in HCC xenograft mouse models. Overall, this study describes a promising nanoparticulate drug co-delivery strategy to combine clinical anticancer drugs and enhance anti-HCC efficacy.
MeSH term(s)	Animals ; Antibiotics, Antineoplastic/administration & dosage ; Antineoplastic Agents/administration & dosage ; Carcinoma, Hepatocellular/drug therapy ; Doxorubicin/administration & dosage ; Humans ; Lipids ; Liver Neoplasms/drug therapy ; Mice ; Nanoparticles ; Niacinamide/administration & dosage ; Niacinamide/analogs & derivatives ; Phenylurea Compounds/administration & dosage ; Polymers
Chemical Substances	Antibiotics, Antineoplastic ; Antineoplastic Agents ; Lipids ; Phenylurea Compounds ; Polymers ; Niacinamide (25X51I8RD4) ; Doxorubicin (80168379AG) ; sorafenib (9ZOQ3TZI87)
Language	English
Publishing date	2016
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2183417-9
ISSN	1549-9642 ; 1549-9634
ISSN (online)	1549-9642
ISSN	1549-9634
DOI	10.1016/j.nano.2016.01.017
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Article ; Online: Preventive effect of non-mitogenic acidic fibroblast growth factor on diabetes-induced testicular cell death.

Skibba, Melissa / Zhang, Chi / Jiang, Xin / Xin, Ying / Cai, Lu

Reproductive toxicology (Elmsford, N.Y.)

2014 Volume 49, Page(s) 136–144

Abstract: Fibroblast growth factor (FGF)-1 was found to protect the heart from oxidative damage, but clinically its long-term use was restricted for its undesirable proliferating activity on cells. Thus a cluster of amino acids responsible for the proliferation ... ...

Abstract	Fibroblast growth factor (FGF)-1 was found to protect the heart from oxidative damage, but clinically its long-term use was restricted for its undesirable proliferating activity on cells. Thus a cluster of amino acids responsible for the proliferation were deleted in the native FGF-1 to create a non-mitogenic FGF-1 (nmFGF-1). Whether the nmFGF-1 protects male germ cells from diabetes-induced apoptotic death was examined in diabetic mice induced with multiple low-doses of streptozotocin, followed by nmFGF-1 treatment for 6 months. Diabetic mice showed a decrease in testicular weight and an increase in apoptotic cell death. Treatment with nmFGF-1 alleviated the diabetic effects on testicular weight and apoptotic cell death. Mechanistically, nmFGF-1 may alleviate diabetes-induced germ cell death by decreasing the BAX/Bcl-2 ratio and endoplasmic reticulum stress as well as associated cell death, which is associated with Nrf-2 activation.
MeSH term(s)	Animals ; Apoptosis/drug effects ; Cell Death/drug effects ; Cell Proliferation/drug effects ; Diabetes Mellitus, Experimental/complications ; Fibroblast Growth Factor 1/pharmacology ; Male ; Mice ; Oxidative Stress/drug effects ; Testis/drug effects
Chemical Substances	Fibroblast Growth Factor 1 (104781-85-3)
Language	English
Publishing date	2014-11
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	639342-1
ISSN	1873-1708 ; 0890-6238
ISSN (online)	1873-1708
ISSN	0890-6238
DOI	10.1016/j.reprotox.2014.08.002
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Zs.A 2316: Show issues

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Article ; Online: Role of the cytochrome P-450/ epoxyeicosatrienoic acids pathway in the pathogenesis of renal dysfunction in cirrhosis.

Yeboah, Michael M / Hye Khan, Md Abdul / Chesnik, Marla A / Skibba, Melissa / Kolb, Lauren L / Imig, John D

Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association

2018 Volume 33, Issue 8, Page(s) 1333–1343

Abstract: Background: Hepatorenal syndrome (HRS) is a life-threatening complication of advanced liver cirrhosis that is characterized by hemodynamic alterations in the kidney and other vascular beds. Cytochrome P(CYP)-450 enzymes metabolize arachidonic acid to ... ...

Abstract	Background: Hepatorenal syndrome (HRS) is a life-threatening complication of advanced liver cirrhosis that is characterized by hemodynamic alterations in the kidney and other vascular beds. Cytochrome P(CYP)-450 enzymes metabolize arachidonic acid to epoxyeicosatrienoic acids (EETs) and 20-hydroxyeicosatetraenoic acids. These eicosanoids regulate blood pressure, vascular tone and renal tubular sodium transport under both physiological and pathophysiological states. Methods: Experiments were performed to investigate the role of the CYP system in the pathogenesis of renal dysfunction during cirrhosis. Rats underwent bile duct ligation (BDL) or sham surgery and were studied at 2, 4 and 5 weeks post-surgery. In additional experiments, post-BDL rats were treated with three daily intraperitoneal doses of either the selective epoxygenase inhibitor N-(methylsulfonyl)-2-(2-propynyloxy)-benzenehexanamide (MSPPOH) or a vehicle, starting on Day 22 after surgery. Results: BDL led to progressive renal dysfunction that was associated with reduced renal cortical perfusion but without any overt histologic changes, consistent with HRS. CYP isoform enzyme expression was significantly altered in BDL rats. In the kidney, CYP2C23 expression was upregulated at both the mRNA and protein levels in BDL rats, while CYP2C11 was downregulated. Histologically, the changes in CYP2C23 and CYP2C11 expression were localized to the renal tubules. EET production was increased in the kidneys of BDL rats as assessed by urinary eicosanoid levels. Finally, treatment with the selective epoxygenase inhibitor MSPPOH significantly reduced renal function and renal cortical perfusion in BDL rats, suggesting a homeostatic role for epoxygenase-derived eicosanoids. Conclusions: The CYP/EET pathway might represent a novel therapeutic target for modulating renal dysfunction in advanced cirrhosis.
MeSH term(s)	Animals ; Cytochrome P-450 Enzyme System/metabolism ; Hydroxyeicosatetraenoic Acids/metabolism ; Kidney Diseases/etiology ; Kidney Diseases/metabolism ; Kidney Diseases/pathology ; Liver Cirrhosis/complications ; Male ; Rats ; Rats, Sprague-Dawley ; Signal Transduction
Chemical Substances	Hydroxyeicosatetraenoic Acids ; 20-hydroxy-5,8,11,14-eicosatetraenoic acid (79551-86-3) ; Cytochrome P-450 Enzyme System (9035-51-2)
Language	English
Publishing date	2018-01-23
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	90594-x
ISSN	1460-2385 ; 0931-0509
ISSN (online)	1460-2385
ISSN	0931-0509
DOI	10.1093/ndt/gfx354
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Zs.A 2198: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MO 329: Show issues

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Article ; Online: A novel dual PPAR-γ agonist/sEH inhibitor treats diabetic complications in a rat model of type 2 diabetes.

Hye Khan, Md Abdul / Kolb, Lauren / Skibba, Melissa / Hartmann, Markus / Blöcher, René / Proschak, Ewgenij / Imig, John D

Diabetologia

2018 Volume 61, Issue 10, Page(s) 2235–2246

Abstract: Aims/hypothesis: The metabolic syndrome is a cluster of risk correlates that can progress to type 2 diabetes. The present study aims to evaluate a novel molecule with a dual action against the metabolic syndrome and type 2 diabetes.: Methods: We ... ...

Abstract	Aims/hypothesis: The metabolic syndrome is a cluster of risk correlates that can progress to type 2 diabetes. The present study aims to evaluate a novel molecule with a dual action against the metabolic syndrome and type 2 diabetes. Methods: We developed and tested a novel dual modulator, RB394, which acts as a soluble epoxide hydrolase (sEH) inhibitor and a peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist in rat models of the metabolic syndrome-the obese spontaneously hypertensive (SHROB) rat and the obese diabetic Zucker fatty/spontaneously hypertensive heart failure F1 hybrid (ZSF1) rat. In SHROB rats we studied the ability of RB394 to prevent metabolic syndrome phenotypes, while in ZSF1 obese diabetic rats we compared RB394 with the ACE inhibitor enalapril in the treatment of type 2 diabetes and associated comorbid conditions. RB394 (10 mg/kg daily) and enalapril (10 mg/kg daily) were administered orally for 8 weeks. Results: RB394 blunted the development of hypertension, insulin resistance, hyperlipidaemia and kidney injury in SHROB rats and reduced fasting blood glucose and HbA Conclusions/interpretation: These findings demonstrate that a novel sHE inhibitor/PPAR-γ agonist molecule targets multiple risk factors of the metabolic syndrome and is a glucose-lowering agent with a strong ability to treat diabetic complications.
MeSH term(s)	Animals ; Diabetes Mellitus, Experimental/complications ; Diabetes Mellitus, Experimental/drug therapy ; Diabetes Mellitus, Type 2/drug therapy ; Diabetic Nephropathies/physiopathology ; Disease Models, Animal ; Enalapril/pharmacology ; Enzyme Inhibitors/pharmacology ; Epoxide Hydrolases/antagonists & inhibitors ; Fatty Liver/drug therapy ; Fatty Liver/pathology ; Glucose Tolerance Test ; Hypertension/drug therapy ; Insulin Resistance ; Kidney Glomerulus/pathology ; Liver Cirrhosis/pathology ; Male ; Metabolic Syndrome/drug therapy ; Mice ; Mice, Inbred C57BL ; Obesity/physiopathology ; PPAR gamma/agonists ; Rats ; Rats, Zucker
Chemical Substances	Enzyme Inhibitors ; PPAR gamma ; Enalapril (69PN84IO1A) ; Epoxide Hydrolases (EC 3.3.2.-) ; EPHX2 protein, rat (EC 3.3.2.10)
Language	English
Publishing date	2018-07-21
Publishing country	Germany
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1694-9
ISSN	1432-0428 ; 0012-186X
ISSN (online)	1432-0428
ISSN	0012-186X
DOI	10.1007/s00125-018-4685-0
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