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Article ; Online: Direct reactivation of a coherent neocortical memory of context.

Cowansage, Kiriana K / Shuman, Tristan / Dillingham, Blythe C / Chang, Allene / Golshani, Peyman / Mayford, Mark

2014 Volume 84, Issue 2, Page(s) 432–441

Abstract: Declarative memories are thought to be stored within anatomically distributed neuronal networks requiring the hippocampus; however, it is unclear how neocortical areas participate in memory at the time of encoding. Here, we use a c-fos-based genetic ... ...

Abstract	Declarative memories are thought to be stored within anatomically distributed neuronal networks requiring the hippocampus; however, it is unclear how neocortical areas participate in memory at the time of encoding. Here, we use a c-fos-based genetic tagging system to selectively express the channelrhodopsin variant, ChEF, and optogenetically reactivate a specific neural ensemble in retrosplenial cortex (RSC) engaged by context fear conditioning. Artificial stimulation of RSC was sufficient to produce both context-specific behavior and downstream cellular activity commensurate with natural experience. Moreover, optogenetically but not contextually elicited responses were insensitive to hippocampal inactivation, suggesting that although the hippocampus is needed to coordinate activation by sensory cues, a higher-order cortical framework can independently subserve learned behavior, even shortly after learning.
MeSH term(s)	Animals ; Behavior, Animal/physiology ; Conditioning, Psychological/physiology ; Cues ; Fear/physiology ; Hippocampus/physiology ; Learning/physiology ; Memory/physiology ; Mice, Inbred C57BL ; Mice, Transgenic ; Neocortex/physiology
Language	English
Publishing date	2014-10-09
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	808167-0
ISSN	1097-4199 ; 0896-6273
ISSN (online)	1097-4199
ISSN	0896-6273
DOI	10.1016/j.neuron.2014.09.022
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Zs.MG 92: Show issues

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Article ; Online: VBP15, a novel dissociative steroid compound, reduces NFκB-induced expression of inflammatory cytokines in vitro and symptoms of murine trinitrobenzene sulfonic acid-induced colitis.

Damsker, Jesse M / Conklin, Laurie S / Sadri, Soheil / Dillingham, Blythe C / Panchapakesan, Karuna / Heier, Christopher R / McCall, John M / Sandler, Anthony D

Inflammation research : official journal of the European Histamine Research Society ... [et al.

2016 Volume 65, Issue 9, Page(s) 737–743

Abstract: Objective and design: The goal of this study was to assess the capacity of VBP15, a dissociative steroidal compound, to reduce pro-inflammatory cytokine expression in vitro, to reduce symptoms of colitis in the trinitrobenzene sulfonic acid-induced ... ...

Abstract	Objective and design: The goal of this study was to assess the capacity of VBP15, a dissociative steroidal compound, to reduce pro-inflammatory cytokine expression in vitro, to reduce symptoms of colitis in the trinitrobenzene sulfonic acid-induced murine model, and to assess the effect of VBP15 on growth stunting in juvenile mice. Materials: In vitro studies were performed in primary human intestinal epithelial cells. Colitis was induced in mice by administering trinitrobenzene sulfonic acid. Growth stunting studies were performed in wild type outbred mice. Treatment: Cells were treated with VBP15 or prednisolone (10 μM) for 24 h. Mice were subjected to 3 days of VBP15 (30 mg/kg) or prednisolone (30 mg/kg) in the colitis study. In the growth stunting study, mice were subjected to VBP15 (10, 30, 45 mg/kg) or prednisolone (10 mg/kg) for 5 weeks. Methods: Cytokines were measured by PCR and via Luminex. Colitis symptoms were evaluated by assessing weight loss, intestinal blood, and stool consistency. Growth stunting was assessed using an electronic caliper. Results: VBP15 significantly reduced the in vitro production of CCL5 (p < 0.001) IL-6 (p < 0.001), IL-8 (p < 0.05) and reduced colitis symptoms (p < 0.05). VBP15 caused less growth stunting than prednisolone (p < 0.001) in juvenile mice. Conclusion: VBP15 may reduce symptoms of IBD, while decreasing or avoiding detrimental side effects.
MeSH term(s)	Animals ; Anti-Inflammatory Agents/pharmacology ; Anti-Inflammatory Agents/therapeutic use ; Body Size/drug effects ; Cells, Cultured ; Colitis/chemically induced ; Colitis/drug therapy ; Colitis/metabolism ; Cytokines/genetics ; Cytokines/metabolism ; Disease Models, Animal ; Epithelial Cells/drug effects ; Epithelial Cells/metabolism ; Female ; Humans ; Male ; Mice, Inbred BALB C ; NF-kappa B/metabolism ; Pregnadienediols/pharmacology ; Pregnadienediols/therapeutic use ; Trinitrobenzenesulfonic Acid
Chemical Substances	Anti-Inflammatory Agents ; Cytokines ; NF-kappa B ; Pregnadienediols ; VBP15 compound ; Trinitrobenzenesulfonic Acid (8T3HQG2ZC4)
Language	English
Publishing date	2016-09
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	1221794-3
ISSN	1420-908X ; 1023-3830
ISSN (online)	1420-908X
ISSN	1023-3830
DOI	10.1007/s00011-016-0956-8
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Article ; Online: Expanding Reactivity in DNA-Encoded Library Synthesis via Reversible Binding of DNA to an Inert Quaternary Ammonium Support.

Flood, Dillon T / Asai, Shota / Zhang, Xuejing / Wang, Jie / Yoon, Leonard / Adams, Zoë C / Dillingham, Blythe C / Sanchez, Brittany B / Vantourout, Julien C / Flanagan, Mark E / Piotrowski, David W / Richardson, Paul / Green, Samantha A / Shenvi, Ryan A / Chen, Jason S / Baran, Phil S / Dawson, Philip E

Journal of the American Chemical Society

2019 Volume 141, Issue 25, Page(s) 9998–10006

Abstract: DNA Encoded Libraries have proven immensely powerful tools for lead identification. The ability to screen billions of compounds at once has spurred increasing interest in DEL development and utilization. Although DEL provides access to libraries of ... ...

Abstract	DNA Encoded Libraries have proven immensely powerful tools for lead identification. The ability to screen billions of compounds at once has spurred increasing interest in DEL development and utilization. Although DEL provides access to libraries of unprecedented size and diversity, the idiosyncratic and hydrophilic nature of the DNA tag severely limits the scope of applicable chemistries. It is known that biomacromolecules can be reversibly, noncovalently adsorbed and eluted from solid supports, and this phenomenon has been utilized to perform synthetic modification of biomolecules in a strategy we have described as reversible adsorption to solid support (RASS). Herein, we present the adaptation of RASS for a DEL setting, which allows reactions to be performed in organic solvents at near anhydrous conditions opening previously inaccessible chemical reactivities to DEL. The RASS approach enabled the rapid development of C(sp
MeSH term(s)	Aniline Compounds/chemical synthesis ; Combinatorial Chemistry Techniques/methods ; DNA/chemistry ; Piperidines/chemical synthesis ; Proof of Concept Study ; Quaternary Ammonium Compounds/chemistry
Chemical Substances	Aniline Compounds ; Piperidines ; Quaternary Ammonium Compounds ; DNA (9007-49-2)
Language	English
Publishing date	2019-06-12
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	3155-0
ISSN	1520-5126 ; 0002-7863
ISSN (online)	1520-5126
ISSN	0002-7863
DOI	10.1021/jacs.9b03774
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Article: Expanding Reactivity in DNA-Encoded Library Synthesis via Reversible Binding of DNA to an Inert Quaternary Ammonium Support

Journal of the American Chemical Society. 2019 May 28, v. 141, no. 25

2019

Abstract	DNA Encoded Libraries have proven immensely powerful tools for lead identification. The ability to screen billions of compounds at once has spurred increasing interest in DEL development and utilization. Although DEL provides access to libraries of unprecedented size and diversity, the idiosyncratic and hydrophilic nature of the DNA tag severely limits the scope of applicable chemistries. It is known that biomacromolecules can be reversibly, noncovalently adsorbed and eluted from solid supports, and this phenomenon has been utilized to perform synthetic modification of biomolecules in a strategy we have described as reversible adsorption to solid support (RASS). Herein, we present the adaptation of RASS for a DEL setting, which allows reactions to be performed in organic solvents at near anhydrous conditions opening previously inaccessible chemical reactivities to DEL. The RASS approach enabled the rapid development of C(sp2)–C(sp3) decarboxylative cross-couplings with broad substrate scope, an electrochemical amination (the first electrochemical synthetic transformation performed in a DEL context), and improved reductive amination conditions. The utility of these reactions was demonstrated through a DEL-rehearsal in which all newly developed chemistries were orchestrated to afford a compound rich in diverse skeletal linkages. We believe that RASS will offer expedient access to new DEL reactivities, expanded chemical space, and ultimately more drug-like libraries.
Keywords	DNA ; adsorption ; amination ; electrochemistry ; hydrophilicity ; lead ; quaternary ammonium compounds ; solvents
Language	English
Dates of publication	2019-0528
Size	p. 9998-10006.
Publishing place	American Chemical Society
Document type	Article
ZDB-ID	3155-0
ISSN	1520-5126 ; 0002-7863
ISSN (online)	1520-5126
ISSN	0002-7863
DOI	10.1021/jacs.9b03774
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Article ; Online: Inhibition of inflammation with celastrol fails to improve muscle function in dysferlin-deficient A/J mice.

Dillingham, Blythe C / Benny Klimek, Margaret E / Gernapudi, Ramkishore / Rayavarapu, Sree / Gallardo, Eduard / Van der Meulen, Jack H / Jordan, Sarah / Ampong, Beryl / Gordish-Dressman, Heather / Spurney, Christopher F / Nagaraju, Kanneboyina

Journal of the neurological sciences

2015 Volume 356, Issue 1-2, Page(s) 157–162

Abstract: The dysferlin-deficient A/J mouse strain represents a homologous model for limb-girdle muscular dystrophy 2B. We evaluated the disease phenotype in 10 month old A/J mice compared to two dysferlin-sufficient, C57BL/6 and A/JOlaHsd, mouse lines to ... ...

Abstract	The dysferlin-deficient A/J mouse strain represents a homologous model for limb-girdle muscular dystrophy 2B. We evaluated the disease phenotype in 10 month old A/J mice compared to two dysferlin-sufficient, C57BL/6 and A/JOlaHsd, mouse lines to determine which functional end-points are sufficiently sensitive to define the disease phenotype for use in preclinical studies in the A/J strain. A/J mice had significantly lower open field behavioral activity (horizontal activity, total distance, movement time and vertical activity) when compared to C57BL/6 and A/JoIaHsd mice. Both A/J and A/JOIaHsd mice showed decreases in latency to fall with rotarod compared to C57BL/6. No changes were detected in grip strength, force measurements or motor coordination between these three groups. Furthermore, we have found that A/J muscle shows significantly increased levels of the pro-inflammatory cytokine TNF-α when compared to C57BL/6 mice, indicating an activation of NF-κB signaling as part of the inflammatory response in dysferlin-deficient muscle. Therefore, we assessed the effect of celastrol (a potent NF-κB inhibitor) on the disease phenotype in female A/J mice. Celastrol treatment for four months significantly reduced the inflammation in A/J muscle; however, it had no beneficial effect in improving muscle function, as assessed by grip strength, open field activity, and in vitro force contraction. In fact, celastrol treated mice showed a decrease in body mass, hindlimb grip strength and maximal EDL force. These findings suggest that inhibition of inflammation alone may not be sufficient to improve the muscle disease phenotype in dysferlin-deficient mice and may require combination therapies that target membrane stability to achieve a functional improvement in skeletal muscle.
MeSH term(s)	Analysis of Variance ; Animals ; Body Weight/drug effects ; Cytokines/metabolism ; Disease Models, Animal ; Dysferlin ; Echocardiography ; Female ; Gene Expression Regulation/drug effects ; In Vitro Techniques ; Inflammation/drug therapy ; Inflammation/etiology ; Male ; Membrane Proteins/deficiency ; Mice ; Mice, Inbred C57BL ; Mice, Mutant Strains ; Muscle Strength/drug effects ; Muscle, Skeletal/drug effects ; Muscle, Skeletal/pathology ; Muscular Dystrophies, Limb-Girdle/complications ; Muscular Dystrophies, Limb-Girdle/drug therapy ; Triterpenes/toxicity
Chemical Substances	Cytokines ; Dysf protein, mouse ; Dysferlin ; Membrane Proteins ; Triterpenes ; celastrol (L8GG98663L)
Language	English
Publishing date	2015-06-24
Publishing country	Netherlands
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	80160-4
ISSN	1878-5883 ; 0022-510X ; 0374-8642
ISSN (online)	1878-5883
ISSN	0022-510X ; 0374-8642
DOI	10.1016/j.jns.2015.06.042
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Article ; Online: VBP15, a novel anti-inflammatory, is effective at reducing the severity of murine experimental autoimmune encephalomyelitis.

Dillingham, Blythe C / Knoblach, Susan M / Many, Gina M / Harmon, Brennan T / Mullen, Amanda M / Heier, Christopher R / Bello, Luca / McCall, John M / Hoffman, Eric P / Connor, Edward M / Nagaraju, Kanneboyina / Reeves, Erica K M / Damsker, Jesse M

Cellular and molecular neurobiology

2015 Volume 35, Issue 3, Page(s) 377–387

Abstract: Multiple sclerosis is a chronic disease of the central nervous system characterized by an autoimmune inflammatory reaction that leads to axonal demyelination and tissue damage. Glucocorticoids, such as prednisolone, are effective in the treatment of ... ...

Abstract	Multiple sclerosis is a chronic disease of the central nervous system characterized by an autoimmune inflammatory reaction that leads to axonal demyelination and tissue damage. Glucocorticoids, such as prednisolone, are effective in the treatment of multiple sclerosis in large part due to their ability to inhibit pro-inflammatory pathways (e.g., NFκB). However, despite their effectiveness, long-term treatment is limited by adverse side effects. VBP15 is a recently described compound synthesized based on the lazeroid steroidal backbone that shows activity in acute and chronic inflammatory conditions, yet displays a much-reduced side effect profile compared to traditional glucocorticoids. The purpose of this study was to determine the effectiveness of VBP15 in inhibiting inflammation and disease progression in experimental autoimmune encephalomyelitis (EAE), a widely used mouse model of multiple sclerosis. Our data show that VBP15 is effective at reducing both disease onset and severity. In parallel studies, we observed that VBP15 was able to inhibit the production of NFκB-regulated pro-inflammatory transcripts in human macrophages. Furthermore, treatment with prednisolone-but not VBP15-increased expression of genes associated with bone loss and muscle atrophy, suggesting lack of side effects of VBP15. These findings suggest that VBP15 may represent a potentially safer alternative to traditional glucocorticoids in the treatment of multiple sclerosis and other inflammatory diseases.
MeSH term(s)	Animals ; Anti-Inflammatory Agents/pharmacology ; Anti-Inflammatory Agents/therapeutic use ; Cells, Cultured ; Dose-Response Relationship, Drug ; Encephalomyelitis, Autoimmune, Experimental/drug therapy ; Encephalomyelitis, Autoimmune, Experimental/pathology ; Female ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; Monocytes/drug effects ; Monocytes/pathology ; Pregnadienediols/pharmacology ; Pregnadienediols/therapeutic use ; Pregnancy ; Severity of Illness Index ; Treatment Outcome
Chemical Substances	Anti-Inflammatory Agents ; Pregnadienediols ; VBP15 compound
Language	English
Publishing date	2015-04
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	283404-2
ISSN	1573-6830 ; 0272-4340
ISSN (online)	1573-6830
ISSN	0272-4340
DOI	10.1007/s10571-014-0133-y
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Article ; Online: Activation of the ubiquitin proteasome pathway in a mouse model of inflammatory myopathy: a potential therapeutic target.

Rayavarapu, Sree / Coley, William / Van der Meulen, Jack H / Cakir, Erdinc / Tappeta, Kathyayini / Kinder, Travis B / Dillingham, Blythe C / Brown, Kristy J / Hathout, Yetrib / Nagaraju, Kanneboyina

Arthritis and rheumatism

2013 Volume 65, Issue 12, Page(s) 3248–3258

Abstract: Objective: Myositis is characterized by severe muscle weakness. We and others have previously shown that endoplasmic reticulum (ER) stress plays a role in the pathogenesis of myositis. The present study was undertaken to identify perturbed pathways and ... ...

Abstract	Objective: Myositis is characterized by severe muscle weakness. We and others have previously shown that endoplasmic reticulum (ER) stress plays a role in the pathogenesis of myositis. The present study was undertaken to identify perturbed pathways and assess their contribution to muscle disease in a mouse myositis model. Methods: Stable isotope labeling with amino acids in cell culture (SILAC) was used to identify alterations in the skeletal muscle proteome of myositic mice in vivo. Differentially altered protein levels identified in the initial comparisons were validated using a liquid chromatography tandem mass spectrometry spike-in strategy and further confirmed by immunoblotting. In addition, we evaluated the effect of a proteasome inhibitor, bortezomib, on the disease phenotype, using well-standardized functional, histologic, and biochemical assessments. Results: With the SILAC technique we identified significant alterations in levels of proteins belonging to the ER stress response, ubiquitin proteasome pathway (UPP), oxidative phosphorylation, glycolysis, cytoskeleton, and muscle contractile apparatus categories. We validated the myositis-related changes in the UPP and demonstrated a significant increase in the ubiquitination of muscle proteins as well as a specific increase in ubiquitin carboxyl-terminal hydrolase isozyme L1 (UCHL-1) in myositis, but not in muscle affected by other dystrophies or normal muscle. Inhibition of the UPP with bortezomib significantly improved muscle function and also significantly reduced tumor necrosis factor α expression in the skeletal muscle of mice with myositis. Conclusion: Our findings indicate that ER stress activates downstream UPPs and contributes to muscle degeneration and that UCHL-1 is a potential biomarker for disease progression. UPP inhibition offers a potential therapeutic strategy for myositis.
MeSH term(s)	Animals ; Boronic Acids/pharmacology ; Bortezomib ; Disease Models, Animal ; Endoplasmic Reticulum Stress/drug effects ; Endoplasmic Reticulum Stress/physiology ; Mice ; Muscle Weakness/metabolism ; Muscle Weakness/pathology ; Muscle, Skeletal/drug effects ; Muscle, Skeletal/metabolism ; Muscle, Skeletal/pathology ; Myositis/metabolism ; Myositis/pathology ; Proteasome Endopeptidase Complex/metabolism ; Proteasome Inhibitors/pharmacology ; Pyrazines/pharmacology ; Signal Transduction/drug effects ; Signal Transduction/physiology ; Ubiquitin/metabolism ; Ubiquitination/drug effects ; Ubiquitination/physiology
Chemical Substances	Boronic Acids ; Proteasome Inhibitors ; Pyrazines ; Ubiquitin ; Bortezomib (69G8BD63PP) ; Proteasome Endopeptidase Complex (EC 3.4.25.1)
Language	English
Publishing date	2013-09-11
Publishing country	United States
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	127294-9
ISSN	1529-0131 ; 0004-3591 ; 2326-5191
ISSN (online)	1529-0131
ISSN	0004-3591 ; 2326-5191
DOI	10.1002/art.38180
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Article ; Online: Δ-9,11 modification of glucocorticoids dissociates nuclear factor-κB inhibitory efficacy from glucocorticoid response element-associated side effects.

Baudy, Andreas R / Reeves, Erica K M / Damsker, Jesse M / Heier, Christopher / Garvin, Lindsay M / Dillingham, Blythe C / McCall, John / Rayavarapu, Sree / Wang, Zuyi / Vandermeulen, Jack H / Sali, Arpana / Jahnke, Vanessa / Duguez, Stephanie / DuBois, Debra / Rose, Mary C / Nagaraju, Kanneboyina / Hoffman, Eric P

The Journal of pharmacology and experimental therapeutics

2012 Volume 343, Issue 1, Page(s) 225–232

Abstract: Glucocorticoids are standard of care for many inflammatory conditions, but chronic use is associated with a broad array of side effects. This has led to a search for dissociative glucocorticoids--drugs able to retain or improve efficacy associated with ... ...

Abstract	Glucocorticoids are standard of care for many inflammatory conditions, but chronic use is associated with a broad array of side effects. This has led to a search for dissociative glucocorticoids--drugs able to retain or improve efficacy associated with transrepression [nuclear factor-κB (NF-κB) inhibition] but with the loss of side effects associated with transactivation (receptor-mediated transcriptional activation through glucocorticoid response element gene promoter elements). We investigated a glucocorticoid derivative with a Δ-9,11 modification as a dissociative steroid. The Δ-9,11 analog showed potent inhibition of tumor necrosis factor-α-induced NF-κB signaling in cell reporter assays, and this transrepression activity was blocked by 17β-hydroxy-11β-[4-dimethylamino phenyl]-17α-[1-propynyl]estra-4,9-dien-3-one (RU-486), showing the requirement for the glucocorticoid receptor (GR). The Δ-9,11 analog induced the nuclear translocation of GR but showed the loss of transactivation as assayed by GR-luciferase constructs as well as mRNA profiles of treated cells. The Δ-9,11 analog was tested for efficacy and side effects in two mouse models of muscular dystrophy: mdx (dystrophin deficiency), and SJL (dysferlin deficiency). Daily oral delivery of the Δ-9,11 analog showed a reduction of muscle inflammation and improvements in multiple muscle function assays yet no reductions in body weight or spleen size, suggesting the loss of key side effects. Our data demonstrate that a Δ-9,11 analog dissociates the GR-mediated transcriptional activities from anti-inflammatory activities. Accordingly, Δ-9,11 analogs may hold promise as a source of safer therapeutic agents for chronic inflammatory disorders.
MeSH term(s)	Animals ; Dose-Response Relationship, Drug ; Dronabinol/analogs & derivatives ; Dronabinol/chemistry ; Dronabinol/pharmacology ; Female ; Glucocorticoids/adverse effects ; Glucocorticoids/pharmacology ; HEK293 Cells ; Humans ; Mice ; Mice, Inbred C57BL ; Mice, Inbred mdx ; Mice, Knockout ; NF-kappa B/antagonists & inhibitors ; NF-kappa B/metabolism ; Response Elements/drug effects ; Response Elements/physiology ; Spleen/drug effects ; Spleen/metabolism ; Treatment Outcome
Chemical Substances	Glucocorticoids ; NF-kappa B ; 11-nor-delta(9)-tetrahydrocannabinol-9-carboxylic acid (4TPC9E4A32) ; Dronabinol (7J8897W37S)
Language	English
Publishing date	2012-06-28
Publishing country	United States
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	3106-9
ISSN	1521-0103 ; 0022-3565
ISSN (online)	1521-0103
ISSN	0022-3565
DOI	10.1124/jpet.112.194340
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Article ; Online: VBP15, a glucocorticoid analogue, is effective at reducing allergic lung inflammation in mice.

PloS one

2013 Volume 8, Issue 5, Page(s) e63871

Abstract: Asthma is a chronic inflammatory condition of the lower respiratory tract associated with airway hyperreactivity and mucus obstruction in which a majority of cases are due to an allergic response to environmental allergens. Glucocorticoids such as ... ...

Abstract	Asthma is a chronic inflammatory condition of the lower respiratory tract associated with airway hyperreactivity and mucus obstruction in which a majority of cases are due to an allergic response to environmental allergens. Glucocorticoids such as prednisone have been standard treatment for many inflammatory diseases for the past 60 years. However, despite their effectiveness, long-term treatment is often limited by adverse side effects believed to be caused by glucocorticoid receptor-mediated gene transcription. This has led to the pursuit of compounds that retain the anti-inflammatory properties yet lack the adverse side effects associated with traditional glucocorticoids. We have developed a novel series of steroidal analogues (VBP compounds) that have been previously shown to maintain anti-inflammatory properties such as NFκB-inhibition without inducing glucocorticoid receptor-mediated gene transcription. This study was undertaken to determine the effectiveness of the lead compound, VBP15, in a mouse model of allergic lung inflammation. We show that VBP15 is as effective as the traditional glucocorticoid, prednisolone, at reducing three major hallmarks of lung inflammation--NFκB activity, leukocyte degranulation, and pro-inflammatory cytokine release from human bronchial epithelial cells obtained from patients with asthma. Moreover, we found that VBP15 is capable of reducing inflammation of the lung in vivo to an extent similar to that of prednisone. We found that prednisolone--but not VBP15 shortens the tibia in mice upon a 5 week treatment regimen suggesting effective dissociation of side effects from efficacy. These findings suggest that VBP15 may represent a potent and safer alternative to traditional glucocorticoids in the treatment of asthma and other inflammatory diseases.
MeSH term(s)	Animals ; Asthma/complications ; Asthma/metabolism ; Asthma/pathology ; Cell Degranulation/drug effects ; Cell Movement/drug effects ; Cytokines/metabolism ; Disease Models, Animal ; Epithelial Cells/drug effects ; Epithelial Cells/metabolism ; Epithelial Cells/pathology ; Female ; Glucocorticoids/chemistry ; Glucocorticoids/pharmacology ; Glucocorticoids/therapeutic use ; Humans ; Hypersensitivity/complications ; Hypersensitivity/drug therapy ; Leukocytes/drug effects ; Leukocytes/physiology ; Lung/drug effects ; Lung/pathology ; Male ; Mice ; Mice, Inbred BALB C ; NF-kappa B/metabolism ; Osteogenesis/drug effects ; Ovalbumin ; Pneumonia/complications ; Pneumonia/drug therapy ; Pregnadienediols/chemistry ; Pregnadienediols/pharmacology ; Pregnadienediols/therapeutic use ; Tibia/drug effects ; Tibia/pathology
Chemical Substances	Cytokines ; Glucocorticoids ; NF-kappa B ; Pregnadienediols ; VBP15 compound ; Ovalbumin (9006-59-1)
Language	English
Publishing date	2013-05-07
Publishing country	United States
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.
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0063871
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Article ; Online: VBP15, a novel anti-inflammatory and membrane-stabilizer, improves muscular dystrophy without side effects.

Heier, Christopher R / Damsker, Jesse M / Yu, Qing / Dillingham, Blythe C / Huynh, Tony / Van der Meulen, Jack H / Sali, Arpana / Miller, Brittany K / Phadke, Aditi / Scheffer, Luana / Quinn, James / Tatem, Kathleen / Jordan, Sarah / Dadgar, Sherry / Rodriguez, Olga C / Albanese, Chris / Calhoun, Michael / Gordish-Dressman, Heather / Jaiswal, Jyoti K /

Connor, Edward M / McCall, John M / Hoffman, Eric P / Reeves, Erica K M / Nagaraju, Kanneboyina

EMBO molecular medicine

2013 Volume 5, Issue 10, Page(s) 1569–1585

Abstract: Absence of dystrophin makes skeletal muscle more susceptible to injury, resulting in breaches of the plasma membrane and chronic inflammation in Duchenne muscular dystrophy (DMD). Current management by glucocorticoids has unclear molecular benefits and ... ...

Abstract	Absence of dystrophin makes skeletal muscle more susceptible to injury, resulting in breaches of the plasma membrane and chronic inflammation in Duchenne muscular dystrophy (DMD). Current management by glucocorticoids has unclear molecular benefits and harsh side effects. It is uncertain whether therapies that avoid hormonal stunting of growth and development, and/or immunosuppression, would be more or less beneficial. Here, we discover an oral drug with mechanisms that provide efficacy through anti-inflammatory signaling and membrane-stabilizing pathways, independent of hormonal or immunosuppressive effects. We find VBP15 protects and promotes efficient repair of skeletal muscle cells upon laser injury, in opposition to prednisolone. Potent inhibition of NF-κB is mediated through protein interactions of the glucocorticoid receptor, however VBP15 shows significantly reduced hormonal receptor transcriptional activity. The translation of these drug mechanisms into DMD model mice improves muscle strength, live-imaging and pathology through both preventive and post-onset intervention regimens. These data demonstrate successful improvement of dystrophy independent of hormonal, growth, or immunosuppressive effects, indicating VBP15 merits clinical investigation for DMD and would benefit other chronic inflammatory diseases.
MeSH term(s)	Animals ; Anti-Inflammatory Agents/pharmacology ; Anti-Inflammatory Agents/toxicity ; Cell Line ; Cell Membrane/drug effects ; Cell Membrane/physiology ; Immunosuppressive Agents/pharmacology ; Immunosuppressive Agents/toxicity ; Lasers ; Mice ; Mice, Inbred mdx ; Muscular Dystrophies/metabolism ; Muscular Dystrophies/pathology ; Myoblasts/cytology ; Myoblasts/drug effects ; Myoblasts/radiation effects ; NF-kappa B/antagonists & inhibitors ; NF-kappa B/metabolism ; Necrosis/etiology ; Phenotype ; Prednisolone/pharmacology ; Prednisolone/toxicity ; Pregnadienediols/pharmacology ; Pregnadienediols/toxicity ; Protein Interaction Maps/drug effects ; Receptors, Glucocorticoid/genetics ; Receptors, Glucocorticoid/metabolism ; Signal Transduction/drug effects ; T-Lymphocytes/drug effects ; T-Lymphocytes/immunology ; Transcription, Genetic/drug effects
Chemical Substances	Anti-Inflammatory Agents ; Immunosuppressive Agents ; NF-kappa B ; Pregnadienediols ; Receptors, Glucocorticoid ; VBP15 compound ; Prednisolone (9PHQ9Y1OLM)
Language	English
Publishing date	2013-09-09
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	2467145-9
ISSN	1757-4684 ; 1757-4676
ISSN (online)	1757-4684
ISSN	1757-4676
DOI	10.1002/emmm.201302621
Database	MEDical Literature Analysis and Retrieval System OnLINE

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