Simultaneous Addition of Shikonin and Its Derivatives with Lipopolysaccharide Induces Rapid Macrophage Death

Abstract

Macrophages play pivotal roles in inflammatory responses. Previous studies showed that various natural products exert antiinflammatory effects by regulating macrophage activation. Recent studies have shown that shikonin (SHK) and its derivatives (β-hydroxyisovalerylshikonin, acetylshikonin, and isobutylshikonin), which are 1,4-naphthoquinone pigments extracted from the roots of Lithospermum erythrorhizon, have various pharmacological, including antiinflammatory and antitumor, effects. Even though there have been many studies on the antiinflammatory activities of SHK derivatives, only a few have described their direct effects on macrophages. We investigated the effects of SHK derivatives on lipopolysaccharide (LPS)-treated macrophages. Low doses of SHK derivatives induced significant macrophage cytotoxicity (mouse macrophage-like J774.1/JA-4 cells and mouse peritoneal macrophages) in the presence of LPS. SHK activated caspases-3 and -7, which led to DNA fragmentation, but this cytotoxicity was prevented through a pan-caspase inhibitor in LPS-treated JA-4 cells. Maximal cytotoxic effects were achieved when SHK was added immediately before LPS addition. These results indicate that SHK derivatives induce caspase-dependent apoptotic cell death of LPS-treated macrophages and suggest that SHK acts during an early stage of LPS signaling.

Pharmacology, toxicity and pharmacokinetics of acetylshikonin: a review

“…Macrophages play an important part in inflammatory responses. Acetylshikonin showed cytotoxic effect on LPS-stimulated macrophages through caspasedependent apoptotic cell death pathway (Koike et al 2016). Zorman et al (2016) demonstrated that acetylshikonin suppressed IL-1b release and the second step of Nod-like receptor protein 3 (NLRP3) inflammasome activation in C57BL/6 mice.…”

“…Acetylshikonin showed cytotoxic effect on LPS-stimulated macrophages through caspase-dependent apoptotic cell death pathway (Koike et al. 2016 ). Zorman et al.…”

Naturally Oxidized Olive Oil Promotes Active Cutaneous Anaphylaxis and Th2 Cytokine Production

“…Non-immunized mice were challenged in the same manner as immunized mice in order to assess nonspecific dye leakage. The extraction and quantification of dye leakage were performed as described by Inagaki et al 18) Blood samples were collected 1 and 2 weeks after OVAimmunization. OVA-specific IgE plasma levels were measured using a commercial enzyme-linked immunosorbent assay (ELISA) kit (SHIBAYAGI Co., Ltd., Gunma, Japan).…”

Effect of β-cyclodextrin encapsulation on cytotoxic activity of acetylshikonin against HCT-116 and MDA-MB-231 cancer cell lines

“…As a natural naphthazarin derivative, acetylshikonin is one of the major ingredients found in red colored root extracts of the plants from family Boraginaceae , genera Alkanna , Onosma , Arnebia , Lithospermum and Echium (Papageorgiou et al, 1999, Cheng et al, 2008, Kretschmer et al, 2012, Skrzypczak et al, 2015, Vukic et al, 2017, Mirzaei et al, 2018). Acetylshikonin rich extracts have valuable usage as natural food colorants (Davis, 1988, Papageorgiou et al, 1999, Davies, 2004), while literature data have revealed that this lipophilic compound exhibits multiple pharmacological effects such as antibacterial (Papageorgiou et al, 1999, Shen et al, 2002, Vukic et al, 2017), cytotoxic (Papageorgiou et al, 1999, Kretschmer et al, 2012, Vukic et al, 2017, Park et al, 2017), anti-inflammatory (Cheng et al, 2008, Koike et al, 2016), antiulcer (Toker et al, 2013), antigenotoxic (Skrzypczak et al, 2015), anti-obesity (Gwon et al, 2012, Su et al, 2016) and antiparasitic (Charan Raja et al, 2016) activities.…”