Inhibition of pSTAT1 by tofacitinib accounts for the early improvement of experimental chronic synovitis

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Fältnamn	Indikatorer	Metadata
000		03815naa a2200445 4500
001		oai:DiVA.org:umu-156597
003		SwePub
008		190220s2019 \| \|\|\|\|\|\|\|\|\|\|\|000 \|\|eng\|
024	7	a https://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-1565972 URI
024	7	a https://doi.org/10.1186/s12950-019-0206-22 DOI
040		a (SwePub)umu
041		a engb eng
042		9 SwePub
072	7	a ref2 swepub-contenttype
072	7	a art2 swepub-publicationtype
100	1	a Perez-Baos, Sandra4 aut
245	1 0	a Inhibition of pSTAT1 by tofacitinib accounts for the early improvement of experimental chronic synovitis
264		c 2019-01-29
264	1	b BioMed Central (BMC),c 2019
338		a electronic2 rdacarrier
520		a Background: In order to gain insight into the early effects drawn by JAK inhibitors on intra-joint JAK/STAT-dependent signaling, we sought synovial activation of STATs and their end-products, along with their modification with tofacitinib (TOFA), at flare-up in antigen induced arthritis (AIA). New Zealand rabbits were randomly assigned to four groups –healthy controls, AIA, TOFA-treated AIA, or TOFA-treated controls–. AIA was induced with 4 weekly intra-articular ovalbumin injections in sensitized animals. TOFA (10 mg·kg− 1·day− 1) was administered for the last 2 weeks. Animals were euthanized 24 h after the last injection.Results: AIA animals showed high-grade synovitis, which was partially improved by TOFA. No effects of the treatment were found on serum C-reactive protein or on the synovial macrophage infiltration at this stage. Synovial MMP-1,-3 and -13 expression levels in treated AIA rabbits were found to drop to those of controls, while a downregulation of IL6, IFNγ and TNF was evident in treated versus untreated AIA rabbits. Concurrently, a reduction in pSTAT1 and SOCS1, but not in pSTAT3, SOCS3 or active NFκB-p65, was noted with TOFA.Conclusions: Studying the mechanism of action of immunomodulatory drugs represents a major challenge in vivo, since drug-dependent decreases in inflammation very likely mask direct effects on disease mechanisms. This study design allowed us to prevent any confounding effect resulting from reductions in the overall inflammatory status, hence assessing the true pharmacological actions of TOFA in a very severe synovitis. Our findings point to pSTAT1 and MMPs as early molecular readouts of response to this JAK inhibitor.
650	7	a MEDICIN OCH HÄLSOVETENSKAPx Klinisk medicinx Reumatologi och inflammation0 (SwePub)302102 hsv//swe
650	7	a MEDICAL AND HEALTH SCIENCESx Clinical Medicinex Rheumatology and Autoimmunity0 (SwePub)302102 hsv//eng
653		a Rheumatoid arthritis
653		a Synovitis
653		a Janus kinase inhibitors
653		a Tofacitinib
700	1	a Gratal, Paula4 aut
700	1	a Barrasa, Juan I.u Umeå universitet,Institutionen för molekylärbiologi (Medicinska fakulteten),Bone and Joint Research Unit, Rheumatology Department, IIS-Fundación Jiménez Díaz UAM, Avenida Reyes Católicos, 2. 28040, Madrid, Spain4 aut
700	1	a Lamuedra, Ana4 aut
700	1	a Sanchez-Pernaute, Olga4 aut
700	1	a Herrero-Beaumont, Gabriel4 aut
700	1	a Largo, Raquel4 aut
710	2	a Umeå universitetb Institutionen för molekylärbiologi (Medicinska fakulteten)4 org
773	0	t Journal of Inflammationd : BioMed Central (BMC)g 16q 16x 1476-9255
856	4	u https://doi.org/10.1186/s12950-019-0206-2y Fulltext
856	4	u https://umu.diva-portal.org/smash/get/diva2:1290445/FULLTEXT01.pdfx primaryx Raw objecty fulltext:print
856	4	u https://doi.org/10.1186/s12950-019-0206-2
856	4 8	u https://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-156597
856	4 8	u https://doi.org/10.1186/s12950-019-0206-2

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Av författaren/redakt...: Perez-Baos, Sand ...; Gratal, Paula; Barrasa, Juan I.; Lamuedra, Ana; Sanchez-Pernaute ...; Herrero-Beaumont ...; visa fler...; Largo, Raquel; visa färre...

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