Rottlerin, a natural polyphenol compound, inhibits upregulation of matrix metalloproteinase-9 and brain astrocytic migration by reducing PKC-δ-dependent ROS signal

Abstract

Background: Upregulation of matrix metalloproteinase-9 (MMP-9) has been indicated as one of the inflammatory biomarkers. In the central nervous system (CNS), the MMP-9 is induced by several proinflammatory mediators and participates in the CNS disorders, including inflammation and neurodegeneration. In addition, protein kinase Cs (PKCs) has been shown to be involved in regulation of various inflammatory factors like MMP-9 by several stimuli in many cell types. Several phytochemicals are believed to reduce the risk of several inflammatory disorders including the CNS diseases. The rottlerin, a principal phenolic compound of the Kamala plant Mallotus philippinensis, has been shown to possess an array of medicinal properties, including anti-PKC-δ, antitumor, anti-oxidative, and antiinflammatory activities. Methods: Herein, we used rat brain astrocytes (RBA) to demonstrate the signaling mechanisms of phorbol 12myristate 13-acetate (PMA)-induced MMP-9 expression by zymographic, RT-PCR, subcellular isolation, Western blot, ROS detection, and promoter reporter analyses. Then, we evaluate the effects of rottlerin on PMA-induced MMP-9 expression in RBA and its influencing mechanism. Results: We first demonstrated that PMA stimulated activation of various types of PKC, including PKC-δ in RBA. Subsequently, PMA induced MMP-9 expression via PKCδ-mediated reactive oxygen species (ROS) generation, extracellular signal-regulated kinase 1/2 (ERK1/2) activation, and then induced c-Fos/AP-1 signaling pathway. Finally, upregulation of MMP-9 by PMA via the pathway may promote astrocytic migration, and the event could be attenuated by rottlerin.

A human-based multi-gene signature enables quantitative drug repurposing for metabolic disease

“…In contrast, bisindolylmaleimide IX, a 20-fold more potent broad-spectrum PKC inhibitor, was inactive in the IR-DR assay, probably reflecting its greater non-specific pharmacology (against other kinase families). Three so-called PKC activators ( French et al, 2020 ; Lee et al, 2020 ) induced negative IR-DR scores (phorbol-12-myristate-13-acetate = –87, ingenol = –96 and prostratin = –97). RNAi targeting of individual PKC isoforms ( clue.io ) demonstrated that the IR-DR assay was sensitive to specific PKC isoformactivity.…”

Anti-Inflammatory Effects of Rhamnetin on Bradykinin-Induced Matrix Metalloproteinase-9 Expression and Cell Migration in Rat Brain Astrocytes

“…These results suggested that the inhibitory effect of RNT on NF-κB activity is involved in the reduction of BK-induced MMP-9 expression and cell migration in RBA-1 cells. In the regulation of MMP-9 expression in RBA-1 cells, activator protein 1 (AP-1) has been unveiled as a key transcription factor [ 67 ]. Whether the inhibitory effects of RNT on MMP-9 expression are caused by suppressing AP-1 activity will be further explored in the future.…”

A systems‐level study reveals host‐targeted repurposable drugs against SARS‐CoV‐2 infection

“…Rottlerin (R077), a natural polyphenolic compound, has been reported to inhibit influenza replication as an inhibitor of PKC (Hoffmann et al , 2008 ), and the translation of rabies virus circle by reducing intracellular ATP contents (Lama et al , 2019 ). It may have neuroprotective effects by its anti‐oxidative and anti‐inflammatory action in the central nervous system (Lee et al , 2020 ). Rottlerin inhibited viral infection but dose‐limiting toxicity prevented a detailed analysis of viral entry vs. infection.…”