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Article: Adenosine receptor modulation: potential implications in veterinary medicine.

Dip, Ramiro G

Veterinary journal (London, England : 1997)

2009 Volume 179, Issue 1, Page(s) 38–49

Abstract: Adenosine is a purine nucleoside whose concentration increases during inflammation and hypoxia and the many roles of this molecule are becoming better understood. Increased reactivity to adenosine of the airways of asthmatic but not of normal subjects ... ...

Abstract	Adenosine is a purine nucleoside whose concentration increases during inflammation and hypoxia and the many roles of this molecule are becoming better understood. Increased reactivity to adenosine of the airways of asthmatic but not of normal subjects underlines the role of adenosine in airway inflammation. The identification and pharmacological characterisation of different adenosine receptors have stimulated the search for subtype-specific ligands able to modulate the effects of this molecule in a directed way. Several compounds of different chemical classes have been identified as having potential drawbacks, including side effects resulting from the broad distribution of the receptors across the organism, have prevented clinical application. In this article, the effects of adenosine's different receptors and the intracellular signalling pathways are reviewed. The potential of adenosine receptor modulation as a therapeutic target for chronic airway inflammation is considered, taking equine recurrent airway disease and feline asthma as examples of naturally occurring airway obstructive diseases. Other potential applications for adenosine receptor modulation are also discussed. As the intrinsic molecular events of adenosine's mechanism of action become uncovered, new concrete therapeutic approaches will become available for the treatment of various conditions in veterinary medicine.
MeSH term(s)	Adenosine/physiology ; Animals ; Asthma/drug therapy ; Asthma/immunology ; Asthma/physiopathology ; Asthma/veterinary ; Bronchoconstriction ; Cat Diseases/drug therapy ; Cat Diseases/immunology ; Cat Diseases/physiopathology ; Cats ; Horse Diseases/drug therapy ; Horse Diseases/immunology ; Horse Diseases/physiopathology ; Horses ; Inflammation ; Pulmonary Disease, Chronic Obstructive/drug therapy ; Pulmonary Disease, Chronic Obstructive/immunology ; Pulmonary Disease, Chronic Obstructive/physiopathology ; Pulmonary Disease, Chronic Obstructive/veterinary ; Purinergic P1 Receptor Agonists ; Purinergic P1 Receptor Antagonists ; Receptors, Purinergic P1/physiology ; Signal Transduction
Chemical Substances	Purinergic P1 Receptor Agonists ; Purinergic P1 Receptor Antagonists ; Receptors, Purinergic P1 ; Adenosine (K72T3FS567)
Language	English
Publishing date	2009-01
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	428614-5
ISSN	1532-2971 ; 1090-0233 ; 0372-5545
ISSN (online)	1532-2971
ISSN	1090-0233 ; 0372-5545
DOI	10.1016/j.tvjl.2007.08.005
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Article: Adenosine receptor modulation: Potential implications in veterinary medicine

Dip, Ramiro G

Veterinary journal. 2009 Jan., v. 179, issue 1

2009

Abstract	Adenosine is a purine nucleoside whose concentration increases during inflammation and hypoxia and the many roles of this molecule are becoming better understood. Increased reactivity to adenosine of the airways of asthmatic but not of normal subjects underlines the role of adenosine in airway inflammation. The identification and pharmacological characterisation of different adenosine receptors have stimulated the search for subtype-specific ligands able to modulate the effects of this molecule in a directed way. Several compounds of different chemical classes have been identified as having potential drawbacks, including side effects resulting from the broad distribution of the receptors across the organism, have prevented clinical application. In this article, the effects of adenosine's different receptors and the intracellular signalling pathways are reviewed. The potential of adenosine receptor modulation as a therapeutic target for chronic airway inflammation is considered, taking equine recurrent airway disease and feline asthma as examples of naturally occurring airway obstructive diseases. Other potential applications for adenosine receptor modulation are also discussed. As the intrinsic molecular events of adenosine's mechanism of action become uncovered, new concrete therapeutic approaches will become available for the treatment of various conditions in veterinary medicine.
Keywords	animals ; adenosine ; receptors ; veterinary medicine ; inflammation ; hypoxia ; biochemical pathways ; bioactive properties ; asthma ; adverse effects ; signal transduction ; cats ; horses ; respiratory tract diseases ; mechanism of action
Language	English
Dates of publication	2009-01
Size	p. 38-49.
Document type	Article
ZDB-ID	428614-5
ISSN	1532-2971 ; 0372-5545 ; 1090-0233
ISSN (online)	1532-2971
ISSN	0372-5545 ; 1090-0233
DOI	10.1016/j.tvjl.2007.08.005
Database	NAL-Catalogue (AGRICOLA)

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Book ; Thesis: The red fox (Vulpes vulpes) as a bioindicator of environmental pollutants in urban areas

Dip, Ramiro

2002

Author's details	vorgelegt von Ramiro Dip
Language	English
Size	III, 51 S, graph. Darst., Kt
Document type	Book ; Thesis
Thesis / German Habilitation thesis	Univ., Diss.--Zürich, 2002
Database	Former special subject collection: coastal and deep sea fishing

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Book ; Thesis: The red fox (Vulpes vulpes) as a bioindicator of environmental pollutants in urban areas

Dip, Ramiro

2002

Author's details	vorgelegt von Ramiro Dip
Language	English
Size	III, 51 S, graph. Darst., Kt
Document type	Book ; Thesis
Thesis / German Habilitation thesis	Univ., Diss.--Zürich, 2002
Database	Special collection on veterinary medicine and general parasitology

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Article ; Online: Selective regulation of nuclear orphan receptors 4A by adenosine receptor subtypes in human mast cells.

Zhang, Li / Paine, Catherine / Dip, Ramiro

Journal of cell communication and signaling

2010 Volume 4, Issue 4, Page(s) 173–183

Abstract: Nuclear orphan receptors 4A (NR4A) are early responsive genes that belong to the superfamily of hormone receptors and comprise NR4A1, NR4A2 and NR4A3. They have been associated to transcriptional activation of multiple genes involved in inflammation, ... ...

Abstract	Nuclear orphan receptors 4A (NR4A) are early responsive genes that belong to the superfamily of hormone receptors and comprise NR4A1, NR4A2 and NR4A3. They have been associated to transcriptional activation of multiple genes involved in inflammation, apoptosis and cell cycle control. Here, we establish a link between NR4As and adenosine, a paradoxical inflammatory molecule that can contribute to persistence of inflammation or mediate inflammatory shutdown. Transcriptomics screening of the human mast cell-line HMC-1 revealed a sharp induction of transcriptionally active NR4A2 and NR4A3 by the adenosine analogue NECA. The concomitant treatment of NECA and the adenosine receptor A(2A) (A(2A)AR) selective antagonist SCH-58261 exaggerated this effect, suggesting that upregulation of these factors in mast cells is mediated by other AR subtypes (A(2B) and A(3)) and that A(2A)AR activation counteracts NR4A2 and NR4A3 induction. In agreement with this, A(2A)AR-silencing amplified NR4A induction by NECA. Interestingly, a similar A(2A)AR modulatory effect was observed on ERK1/2 phosphorylation because A(2A)AR blockage exacerbated NECA-mediated phosphorylation of ERK1/2. In addition, PKC or MEK1/2 inhibition prevented ERK1/2 phosphorylation and antagonized AR-mediated induction of NR4A2 and NR4A3, suggesting the involvement of these kinases in AR to NR4A signaling. Finally, we observed that selective A(2A)AR activation with CGS-21680 blocked PMA-induced ERK1/2 phosphorylation and modulated the overexpression of functional nuclear orphan receptors 4A. Taken together, these results establish a novel PKC/ERK/nuclear orphan receptors 4A axis for adenosinergic signaling in mast cells, which can be modulated by A(2A)AR activation, not only in the context of adenosine but of other mast cell activating stimuli as well.
Language	English
Publishing date	2010-11-03
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	2299380-0
ISSN	1873-961X ; 1873-9601
ISSN (online)	1873-961X
ISSN	1873-9601
DOI	10.1007/s12079-010-0104-0
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Article ; Audio / Video: Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens

Dip, Ramiro / Lenz, Sarah / Gmuender, Hans / Naegeli, Hanspeter

Food and chemical toxicology. 2009 Apr., v. 47, issue 4

2009

Keywords	pleiotropy ; transcriptome ; transcriptomics ; breast neoplasms ; cell culture ; cytotoxicity ; human cell lines ; plant estrogens ; gene expression ; resveratrol ; viability ; hormone receptors
Language	English
Dates of publication	2009-04
Size	p. 787-795.
Document type	Article ; Audio / Video
ZDB-ID	782617-5
ISSN	1873-6351 ; 0278-6915
ISSN (online)	1873-6351
ISSN	0278-6915
DOI	10.1016/j.fct.2009.01.008
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: More than just strand breaks: the recognition of structural DNA discontinuities by DNA-dependent protein kinase catalytic subunit.

Dip, Ramiro / Naegeli, Hanspeter

FASEB journal : official publication of the Federation of American Societies for Experimental Biology

2005 Volume 19, Issue 7, Page(s) 704–715

Abstract: The DNA-dependent protein kinase (DNA-PK) is a trimeric factor originally identified as an enzyme that becomes activated upon incubation with DNA. Genetic defects in either the catalytic subunit (DNA-PK(CS)) or the two Ku components of DNA-PK result in ... ...

Abstract	The DNA-dependent protein kinase (DNA-PK) is a trimeric factor originally identified as an enzyme that becomes activated upon incubation with DNA. Genetic defects in either the catalytic subunit (DNA-PK(CS)) or the two Ku components of DNA-PK result in immunodeficiency, radiosensitivity, and premature aging. This combined phenotype is generally attributed to the requirement for DNA-PK in the repair of DNA double strand breaks during various biological processes. However, recent studies revealed that DNA-PK(CS), a member of the growing family of phosphatidylinositol 3-kinases, participates in signal transduction cascades related to apoptotic cell death, telomere maintenance and other pathways of genome surveillance. These manifold functions of DNA-PK(CS) have been associated with an increasing number of protein interaction partners and phosphorylation targets. Here we review the DNA binding properties of DNA-PK(CS) and highlight its ability to interact with an astounding diversity of nucleic acid substrates. This survey indicates that the large catalytic subunit of DNA-PK functions as a sensor of not only broken DNA molecules, but of a wider spectrum of aberrant, unusual, or specialized structures that interrupt the standard double helical conformation of DNA.
MeSH term(s)	Catalytic Domain/genetics ; Catalytic Domain/physiology ; DNA/chemistry ; DNA/metabolism ; DNA Repair ; DNA, Cruciform/chemistry ; DNA, Cruciform/metabolism ; DNA-Activated Protein Kinase/chemistry ; DNA-Activated Protein Kinase/metabolism ; Enzyme Activation ; Homeostasis ; Models, Molecular ; Nucleic Acid Conformation ; Phosphorylation ; Recombination, Genetic ; Signal Transduction ; Structure-Activity Relationship ; Substrate Specificity ; Telomere
Chemical Substances	DNA, Cruciform ; DNA (9007-49-2) ; DNA-Activated Protein Kinase (EC 2.7.11.1)
Language	English
Publishing date	2005-05
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	639186-2
ISSN	1530-6860 ; 0892-6638
ISSN (online)	1530-6860
ISSN	0892-6638
DOI	10.1096/fj.04-3041rev
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Article ; Online: Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens.

Dip, Ramiro / Lenz, Sarah / Gmuender, Hans / Naegeli, Hanspeter

Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association

2009 Volume 47, Issue 4, Page(s) 787–795

Abstract: Combinations of estrogen receptor agonists have been shown to exert more potent effects than single compounds in many single-endpoint bioassays. However, to our knowledge, it has never been tested how genome-wide expression programs are shaped by the ... ...

Abstract	Combinations of estrogen receptor agonists have been shown to exert more potent effects than single compounds in many single-endpoint bioassays. However, to our knowledge, it has never been tested how genome-wide expression programs are shaped by the interplay of multiple estrogenic stimuli. In view of the abundance of dietary phytoestrogens, we selected binary mixtures of these phytochemicals to determine their global impact using high-density DNA microarrays. MCF7 cells, a frequent in vitro model for molecular processes associated with breast cancer, were exposed to a sub-saturating concentration of coumestrol either alone or in combination with analogs that exhibit 1000-fold lower estrogen receptor activity. As expected, in the presence of coumestrol, the induction of many estrogen-sensitive genes was not further increased by the addition of resveratrol or enterolactone. However, it was surprising to find that these weak phytoestrogens, when combined with coumestrol in equal concentrations, were able to more than double the number of significantly regulated transcripts. Thus, phytoestrogens with low receptor affinity interact with other estrogenic agonists to generate more widespread expression fingerprints. This effect involving the number of susceptible transcripts instead of their amplitude of induction remains undetected if mixtures are evaluated with conventional bioassays.
MeSH term(s)	Breast Neoplasms/genetics ; Breast Neoplasms/pathology ; Cell Survival/drug effects ; Diet ; Female ; Gene Expression Profiling ; Humans ; Phytoestrogens/pharmacology ; Receptors, Estrogen/drug effects ; Receptors, Estrogen/physiology ; Tumor Cells, Cultured
Chemical Substances	Phytoestrogens ; Receptors, Estrogen
Language	English
Publishing date	2009-04
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	782617-5
ISSN	1873-6351 ; 0278-6915
ISSN (online)	1873-6351
ISSN	0278-6915
DOI	10.1016/j.fct.2009.01.008
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Article ; Online: Binding of the DNA-dependent protein kinase catalytic subunit to Holliday junctions.

Dip, Ramiro / Naegeli, Hanspeter

The Biochemical journal

2004 Volume 381, Issue Pt 1, Page(s) 165–174

Abstract: DNA-PK (DNA-dependent protein kinase) is a double-strand break sensor involved in DNA repair and signal transduction. In the present study, we constructed site-directed cross-linking probes to explore the range of DNA discontinuities that are recognized ... ...

Abstract	DNA-PK (DNA-dependent protein kinase) is a double-strand break sensor involved in DNA repair and signal transduction. In the present study, we constructed site-directed cross-linking probes to explore the range of DNA discontinuities that are recognized by DNA-PK(CS) (DNA-PK catalytic subunit). A comparison between different substrate architectures showed that DNA-PK(CS) associates preferentially with the crossover region of synthetic Holliday junctions. This interaction with four-way junctions was preserved when biotin-streptavidin complexes were assembled at the termini to exclude the binding of Ku proteins. The association of DNA-PK(CS) with Holliday junctions was salt-labile even in the presence of Ku proteins, but this interaction could be stabilized when the DNA probes were incubated with the endogenous enzyme in nuclear extracts of human cells. Cross-linking of the endogenous enzyme in cellular extracts also demonstrated that DNA-PK(CS) binds to DNA ends and four-way junctions with similar affinities in the context of a nuclear protein environment. Kinase assays using p53 proteins as a substrate showed that, in association with four-way structures, DNA-PK(CS) adopts an active conformation different from that in the complex with linear DNA. Our results are consistent with a structure-specific, but Ku- and DNA end-independent, recruitment of DNA-PK(CS) to Holliday junction intermediates. This observation suggests an unexpected functional link between the two main pathways that are responsible for the repair of DNA double-strand breaks in mammalian cells.
MeSH term(s)	Azides/metabolism ; Binding Sites ; Catalytic Domain/radiation effects ; Cell Extracts/chemistry ; Cell Line, Tumor ; Cell Nucleus/chemistry ; Cell Nucleus/pathology ; Cross-Linking Reagents/metabolism ; DNA, Neoplasm/chemistry ; DNA, Neoplasm/metabolism ; DNA-Activated Protein Kinase ; DNA-Binding Proteins ; HeLa Cells/chemistry ; HeLa Cells/metabolism ; HeLa Cells/pathology ; Humans ; Macromolecular Substances ; Nuclear Proteins ; Nucleic Acid Conformation/radiation effects ; Nucleoproteins/metabolism ; Nucleoproteins/physiology ; Protein Binding/radiation effects ; Protein-Serine-Threonine Kinases/chemistry ; Protein-Serine-Threonine Kinases/metabolism ; Recombination, Genetic/genetics ; Recombination, Genetic/radiation effects ; Structure-Activity Relationship ; Ultraviolet Rays
Chemical Substances	Azides ; Cell Extracts ; Cross-Linking Reagents ; DNA, Neoplasm ; DNA-Binding Proteins ; Macromolecular Substances ; Nuclear Proteins ; Nucleoproteins ; DNA-Activated Protein Kinase (EC 2.7.11.1) ; PRKDC protein, human (EC 2.7.11.1) ; Protein-Serine-Threonine Kinases (EC 2.7.11.1)
Language	English
Publishing date	2004-07-01
Publishing country	England
Document type	Comparative Study ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2969-5
ISSN	1470-8728 ; 0006-2936 ; 0306-3275 ; 0264-6021
ISSN (online)	1470-8728
ISSN	0006-2936 ; 0306-3275 ; 0264-6021
DOI	10.1042/BJ20031666
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Article: Concurrent short-term use of prednisolone with cyclosporine A accelerates pruritus reduction and improvement in clinical scoring in dogs with atopic dermatitis

Dip, Ramiro / Carmichael, James / Letellier, Ingrid / Strehlau, Guenther / Roberts, Elizabeth / Bensignor, Emmanuel / Rosenkrantz, Wayne

BMC veterinary research. 2013 Dec., v. 9, no. 1

2013

Abstract: BACKGROUND: A randomized, unmasked, multicenter study was conducted to evaluate the rate of pruritus reduction and improvement in clinical scoring by cyclosporine A (5� mg/kg orally, once daily for 28� days) either alone (n = 25 dogs) or with concurrent ... ...

Abstract	BACKGROUND: A randomized, unmasked, multicenter study was conducted to evaluate the rate of pruritus reduction and improvement in clinical scoring by cyclosporine A (5� mg/kg orally, once daily for 28� days) either alone (n = 25 dogs) or with concurrent prednisolone (1� mg/kg once daily for 7� days, followed by alternate dosing for 14� days; n = 23 dogs) for the treatment of atopic dermatitis in dogs. Dogs were included in the study after exclusion of other causes of pruritic dermatitis, and were assessed by dermatologists on days 0, 14 ± 1 and 28 ± 2. Assessments included: general physical examination, CADESI-03 lesion scoring, overall clinical response, evaluation of adverse events (AEs), body weight and clinical pathology (hematology, clinical chemistry and urinalysis). Owner assessments, including pruritus (visual analogue scale, VAS) and overall assessment of response were conducted every 3–4� days, either during visits to the clinic or at home. Owners reported AEs to the investigator throughout the study. RESULTS: By day 28 ± 2 both treatment groups resulted in a significant improvement of the atopic dermatitis. Both investigators and owners agreed that concurrent therapy resulted in a quicker improvement of the dogs ‘overall’ skin condition and of pruritus (significant reduction of pruritus by day 3–4, 72.8% improvement by day 14 ± 1), when compared to cyclosporine A alone (significant reduction of pruritus by day 7–8, 24.7% improvement by day 14 ± 1). CADESI-03 scores significantly improved in both groups by day 14 ± 1 onwards, and there were no significant differences in the scores between treatment groups at any time points. A total of 56 AEs (cyclosporine A alone = 34; concurrent therapy = 22) were reported in 33 dogs. No dogs died or stopped treatment due to an AE. The most commonly reported AEs in the cyclosporine A group were associated with the digestive tract, whilst systemic disorders were reported more frequently observed following concurrent therapy. Evaluation of body weight change and clinical pathology indices showed no overall clinically significant abnormalities. CONCLUSIONS: In dogs with atopic dermatitis, a short initiating course of prednisolone expedited the efficacy of cyclosporine A in resolving pruritus and associated clinical signs. The observed adverse events were consistent with those expected for the individual veterinary medicinal products.
Keywords	atopic dermatitis ; body weight ; chemistry ; clinical examination ; cyclosporine ; digestive tract ; dogs ; hematology ; prednisolone ; pruritus ; therapeutics ; urinalysis
Language	English
Dates of publication	2013-12
Size	p. 743.
Publishing place	Springer-Verlag
Document type	Article
ISSN	1746-6148
DOI	10.1186/1746-6148-9-173
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