Shikonin extracted from medicinal Chinese herbs exerts anti-inflammatory effect via proteasome inhibition

Abstract

Shikonin, extracted from medicinal Chinese herb (Lithospermum erythrorhizo), was reported to exert anti-inflammatory and anti-cancer effects both in vitro and in vivo. We have found that proteasome was a molecular target of shikonin in tumor cells, but whether shikonin targets macrophage proteasome needs to be investigated. In the current study, we report that shikonin inhibited inflammation in mouse models as efficiently as dexamethasone. Shikonin at 4 μM reduced the Lipopolysaccharides (LPS)-mediated TNFα release in rat primary macrophage cultures, and blocked the translocation of p65-NF-κB from the cytoplasm to the nucleus, associated with decreased proteasomal activity. Consistently, shikonin accumulated IκB-α, an inhibitor of NF-κB, and ubiquitinated proteins in rat primary macrophage cultures, demonstrating that the proteasome is a target of shikonin under inflammatory conditions. Shikonin also induced macrophage cell apoptosis and cell death. These results demonstrate for the first time that proteasome inhibition by shikonin contributes to its anti-inflammatory effect. The novel finding about macrophage proteasome as a target of shikonin suggests that this medicinal compound has great potential to be developed into an anti-inflammatory agent.

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

“…Treatment with SHK reportedly caused cell death in various cancer cell lines, and a low dose of SHK (<3 µM) induced apoptosis in a human non-small cell lung cancer cell line, A549. 26) Consistent with those reports, our time-course study indicated that decreased viability was associated with DNA fragmentation and caspase-3/7 cleavage (Fig. 2).…”

Shikonin inhibits inflammatory responses in rabbit chondrocytes and shows chondroprotection in osteoarthritic rabbit knee

“…Therefore, in this study, we explored the effects of shikonin on IκBα degradation to examine its potential influence on NF-κB. The result showed that shikonin could antagonize the degradation of IκBα in IL-1β induced chondrocytes which also mirrored a previous study conducted in macrophage [17]. The elevated expression of IκBα induced by shikonin would appear to be beneficial for OA chondrocytes.…”

“…It has various pharmacological properties, such as wound healing [13], anti-tumor [14], antioxidant [15] and anti-inflammatory [16,17] properties. The antiinflammatory effect of shikonin was blocking NF-κB p65 translocation from cytoplasm to nucleus by accumulating high levels of IκBα protein in macrophages [17]. However, the effect of shikonin on the equilibrium between synthesis and degradation of cartilage ECM to IL-1β stimulation or its efficacy in OA treatment has not been authenticated.…”

Two new dimeric naphthoquinones with neuraminidase inhibitory activity fromLithospermum erythrorhizon

“…The red pigments from the roots of L. erythrorhizon have been used since ancient times as dyestuffs for fabrics, cosmetics and food (Chang et al 2008), and as crude drugs for anti-inflammatory ointment (Ito et al 2011). It exhibits biological activities such as wound healing (Yin et al 2013), antioxidant (Weng et al 2000), antifungal and antitumour (Han et al 2008;Yang et al 2009;Lu et al 2011;Andujar et al 2013). Previous phytochemical studies reported that the red pigments of L. erythrorhizon were mainly composed of naphthoquinone compounds, such as b-hydroxyisovalerylshikonin, acetylshikonin (Gwon et al 2012), propionylshikonin (Cho et al 1999), isobutyrylshikonin (Syklowska-Baranek et al 2012), b,b-dimethylacryloylshikonin (Li et al 2012, isovalerylshikonin, isobutyrylshikonin (Zhao et al 2011) and a-methylbutyrylshikonin.…”