Anti-inflammatory and cytoprotective polypharmacology of Canephron N reveals targeting of the IKK-NF-κB and p38-MK2-RIPK1 axes

Marija Milosevic; Alexander Magnutzki; Theodor Braun; Shah Hussain; Thomas Jakschitz; Martin Kragl; Michael Soeberdt; Bernhard Nausch; Günther K Bonn; Lukas A Huber; Taras Valovka

doi:10.1016/j.biopha.2024.117747

Anti-inflammatory and cytoprotective polypharmacology of Canephron N reveals targeting of the IKK-NF-κB and p38-MK2-RIPK1 axes

Biomed Pharmacother. 2024 Dec 12:182:117747. doi: 10.1016/j.biopha.2024.117747. Online ahead of print.

Affiliations

¹ ADSI-Austrian Drug Screening Institute, Leopold-Franzens University of Innsbruck, Innsbruck 6020, Austria.
² Bionorica SE, Neumarkt 92318, Germany.
³ ADSI-Austrian Drug Screening Institute, Leopold-Franzens University of Innsbruck, Innsbruck 6020, Austria. Electronic address: guenther.bonn@adsi.ac.at.
⁴ Institute of Cell Biology, Biocenter, Medical University of Innsbruck, Innsbruck 6020, Austria; ADSI-Austrian Drug Screening Institute, Leopold-Franzens University of Innsbruck, Innsbruck 6020, Austria. Electronic address: lukas.a.huber@i-med.ac.at.
⁵ Institute of Cell Biology, Biocenter, Medical University of Innsbruck, Innsbruck 6020, Austria; Department of Pediatrics I, Medical University of Innsbruck, Innsbruck 6020, Austria. Electronic address: taras.valovka@i-med.ac.at.

PMID: 39671726
DOI: 10.1016/j.biopha.2024.117747

Abstract

Urinary tract infections are among the most frequently occurring forms of infection, and inflammation and tissue damage contribute significantly to symptoms, e.g., dysuria and urge. Canephron N is an orally bioavailable herbal medicine with anti-inflammatory, spasmolytic, anti-adhesive, and anti-nociceptive therapeutic effects that is approved for the treatment of uncomplicated urinary tract infections. Here, we used renal tubular epithelial HK-2 cells to study the anti-inflammatory and cytoprotective effects and molecular mechanisms of its active component, BNO 2103. BNO 2103 suppressed nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation by lipopolysaccharide (LPS) and tumor necrosis factor alpha (TNFα) and prevented inhibitory κB kinase (IKK)-dependent phosphorylation and degradation of inhibitor of nuclear factor kappa B alpha (IκBα). BNO 2103 also suppressed the inflammation-specific S536 phosphorylation of the NF-κB subunit p65 and the production of a specific set of inflammatory cytokines. Unlike other NF-κB inhibitors, BNO 2103 demonstrated cytoprotection against TNFα-induced cytotoxicity. Our data suggest that BNO 2103 acts primarily through the mitogen-activated protein kinase p38 (p38 MAPK)-MAPK-activated protein kinase 2 (MK2) axis by promoting receptor-interacting serine/threonine protein kinase 1 (RIPK1) phosphorylation at S320. Simultaneously, it suppresses S166 autophosphorylation and subsequent activation of RIPK1, which is required for apoptotic and necroptotic responses to TNFα. This study confirms Canephron N as an effective alternative to traditional anti-inflammatory drugs and provides initial evidence of its ability to inhibit apoptosis and necroptosis in the urogenital system. It also presents a detailed pathway investigation that identifies the specific targets of Canephron N within the NF-κB signaling cascade.

Keywords: Herbal medicines; Inflammation; Necroptosis; Nuclear transcription factor kappa B; Receptor-interacting serine/threonine protein kinase 1; Urinary tract infection.