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Novel purine analog...
Novel purine analogues regulate IL-1β release via inhibition of JAK activity in human aortic smooth muscle cells
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- Paramel Varghese, Geena, 1985- (author)
- Örebro universitet,Institutionen för medicinska vetenskaper,Cardiovascular Research Centre
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- Lindkvist, Madelene, 1984- (author)
- Örebro universitet,Institutionen för medicinska vetenskaper,Cardiovascular Research Centre
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- Idosa, Berhane A. (author)
- School of Medical Sciences, Örebro University, Örebro, Sweden,Cardiovascular Research Centre
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- Sebina, Laila Sharon (author)
- School of Medical Sciences, Örebro University, Örebro, Sweden,Cardiovascular Research Centre
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- Kardeby, Caroline, 1989- (author)
- School of Medical Sciences, Örebro University, Örebro, Sweden; Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, West Midlands, United Kingdom,Cardiovascular Research Centre
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- Fotopoulou, Theano (author)
- Institute of Chemical Biology, National Hellenic Research Foundation, Athens, Greece
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- Pournara, Dimitra (author)
- Institute of Chemical Biology, National Hellenic Resear
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- Kritsi, Eftichia (author)
- Institute of Chemical Biology, National Hellenic Resear
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- Ifanti, Eleni (author)
- Institute of Chemical Biology, National Hellenic Resear
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- Zervou, Maria (author)
- Institute of Chemical Biology, National Hellenic Resear
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- Koufaki, Maria (author)
- Institute of Chemical Biology, National Hellenic Resear
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- Grenegård, Magnus, 1963- (author)
- Örebro universitet,Institutionen för medicinska vetenskaper,Cardiovascular Research Centre
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- Fransén, Karin, 1973- (author)
- Örebro universitet,Institutionen för medicinska vetenskaper
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(creator_code:org_t)
- Elsevier, 2022
- 2022
- English.
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In: European Journal of Pharmacology. - : Elsevier. - 0014-2999 .- 1879-0712. ; 929
- Related links:
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https://doi.org/10.1...
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Subject headings
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- Purine analogues bearing a nitrate ester motif were previously discovered as cardioprotective and anti-inflammatory agents, but the anti-inflammatory mechanism remains to be established. We therefore investigated the anti-inflammatory effect of two purine analogues, MK118 bearing a nitrate ester moiety and the methyl-substituted analogue MK196 in Aortic Smooth Muscle Cells (AoSMCs), with emphasis on IL-1β release. The AoSMCs were stimulated with LPS with or without purine analogue, followed by ELISA, Olink proteomics, Western blot and real time PCR of NLRP3 inflammasome components. Both purine analogues inhibited the release of proteins involved in inflammation, such as TRAIL, CCL4, CSF1 and IL-1β in AoSMCs, as well as intracellular gene and protein expression of IL-1β and NLRP3 inflammasome components. MK196, but not MK118, also inhibited the LPS-induced release of IL-7, CXCL10, PD-L1, FLT3L and CCL20. We also showed that MK118 and possibly MK196 act via inhibition of JAKs. In silico studies showed that the purine moiety is a competent hinge binding motif and that the purine-piperazine scaffold is well accommodated in the lipophilic groove of JAK1-3. Both compounds establish interactions with catalytic amino acids in the active site of JAK1-3 and the terminal nitrate ester of MK118 was revealed as a promising pharmacophore. Our data suggest that MK118 and MK196 inhibit the release of proinflammatory proteins in AoSMCs, and targets JAK1-3 activation. Purine analogues also inhibit the expression of NLRP3 inflammasome genes and proteins and may in the future be evaluated for anti-inflammatory aspects on inflammatory diseases.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Reumatologi och inflammation (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Rheumatology and Autoimmunity (hsv//eng)
Keyword
- Atherosclerosis
- IL-1β
- Inflammation
- JAK inhibitor
- NLRP3 inflammasome
- Purine analogue
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Paramel Varghese ...
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Lindkvist, Madel ...
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Idosa, Berhane A ...
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Sebina, Laila Sh ...
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Kardeby, Carolin ...
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Fotopoulou, Thea ...
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show more...
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Pournara, Dimitr ...
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Kritsi, Eftichia
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Ifanti, Eleni
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Zervou, Maria
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Koufaki, Maria
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Grenegård, Magnu ...
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Fransén, Karin, ...
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Rheumatology and ...
- Articles in the publication
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European Journal ...
- By the university
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Örebro University