Εξειδίκευση τύπου :	Άρθρο σε επιστημονικό περιοδικό
Τίτλος:	Novel purine analogues regulate IL-1β release via inhibition of JAK activity in human aortic smooth muscle cells
Δημιουργός/Συγγραφέας:	Paramel, Geena V Lindkvist, Madelene Idosa, Berhane A Sebina, Laila Sharon Kardeby, Caroline Fotopoulou, Theano Pournara, Dimitra Kritsi, Eftichia Ifanti, Eleni [EL] Ζερβού, Μαρία[EN] Zervou, Maria [EL] Κουφάκη, Μαρία[EN] Koufaki, Maria Grenegård, Magnus Fransén, Karin
Χορηγός :	Stiftelsen för Kunskaps- och Kompetensutveckling Örebro Universitet Alexander S. Onassis Public Benefit Foundation
Ημερομηνία:	2022-08-15
Γλώσσα:	Αγγλικά
ISSN:	00142999
DOI:	10.1016/j.ejphar.2022.175128
Άλλο:	35792171
Περίληψη:	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.
Τίτλος πηγής δημοσίευσης:	European journal of pharmacology
Τόμος/Κεφάλαιο:	929
Θεματική Κατηγορία:	[EL] Βιοχημεία[EN] Biochemistry [EL] Φαρμακευτική χημεία[EN] Pharmaceutical chemistry [EL] Θεραπευτική. Φαρμακολογία[EN] Therapeutics.Pharmacology [EL] Χημική Βιολογία[EN] Chemical Biology [EL] Δομική Βιολογία[EN] Structural Biology [EL] Κυτταρολογία[EN] Cytology
Λέξεις-Κλειδιά:	Atherosclerosis IL-1β Inflammation JAK inhibitor NLRP3 inflammasome Purine analogue
EU Grant identifier:	HÖG2017 #20170191 HÖG2019 #20190088 #2019-06-13
Κάτοχος πνευματικών δικαιωμάτων:	© 2022 The Authors. Published by Elsevier B.V.
Όροι και προϋποθέσεις δικαιωμάτων:	This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)
Ηλεκτρονική διεύθυνση στον εκδότη (link):	https://www.sciencedirect.com/science/article/pii/S0014299922003892?pes=vor#gs2
Εμφανίζεται στις συλλογές:	Ινστιτούτο Χημικής Βιολογίας - Επιστημονικό έργο