Tetracyclic 1,4-Naphthoquinone Thioglucoside Conjugate U-556 Blocks the Purinergic P2X7 Receptor in Macrophages and Exhibits Anti-Inflammatory Activity In Vivo.
Sergei A KozlovskiyEvgeny A PislyaginEkaterina MenchinskayaEkaterina ChingizovaLeonid A KaluzhskiyAlexis S IvanovGalina N LikhatskayaIrina AgafonovaYuriy E SabutskiSergey PolonikIgor ManzhuloDmitry L AmininPublished in: International journal of molecular sciences (2023)
P2X7 receptors (P2X7Rs) are ligand-gated ion channels that play a significant role in inflammation and are considered a potential therapeutic target for some inflammatory diseases. We have previously shown that a number of synthetic 1,4-naphthoquinones are capable of blocking P2X7Rs in neuronal and macrophage cells. In the present investigation, we have demonstrated the ability of the tetracyclic quinone-thioglucoside conjugate U-556 , derived from 1,4-naphthoquinone thioglucoside, to inhibit ATP-induced Ca 2+ influx and YO-PRO-1 dye uptake, which indicates blocking P2X7R in RAW 264.7 macrophages. This process was accompanied by the inhibition of ATP-induced reactive oxygen species production in macrophages, as well as the macrophage survival strengthening under ATP toxic effects. Nevertheless, U-556 had no noticeable antioxidant capacity. Naphthoquinone-thioglucoside conjugate U-556 binding to the extracellular part of the P2X7R was confirmed by SPR analysis, and the kinetic characteristics of this complex formation were established. Computer modeling predicted that U-556 binds the P2X7R allosteric binding site, topographically similar to that of the specific A438079 blocker. The study of biological activity in in vivo experiments shows that tetracylic conjugate significantly reduces inflammation provoked by carrageenan. The data obtained points out that the observed physiological effects of U-556 may be due to its ability to block the functioning of the P2X7R.
Keyphrases
- oxidative stress
- diabetic rats
- cancer therapy
- reactive oxygen species
- high glucose
- induced apoptosis
- adipose tissue
- drug induced
- electronic health record
- drug delivery
- risk assessment
- cell cycle arrest
- machine learning
- signaling pathway
- big data
- anti inflammatory
- cell proliferation
- binding protein
- climate change
- human health
- endoplasmic reticulum stress
- pi k akt
- free survival