Syk/Src Pathway-Targeted Inhibition of Skin Inflammatory Responses by Carnosic Acid

Abstract

Carnosic acid (CA) is a diterpene compound exhibiting antioxidative, anticancer, anti-angiogenic, anti-inflammatory, anti-metabolic disorder, and hepatoprotective and neuroprotective activities. In this study, the effect of CA on various skin inflammatory responses and its inhibitory mechanism were examined. CA strongly suppressed the production of IL-6, IL-8, and MCP-1 from keratinocyte HaCaT cells stimulated with sodium lauryl sulfate (SLS) and retinoic acid (RA). In addition, CA blocked the release of nitric oxide (NO), tumor necrosis factor (TNF)-α, and prostaglandin E2 (PGE2) from RAW264.7 cells activated by the toll-like receptor (TLR)-2 ligands, Gram-positive bacterium-derived peptidoglycan (PGN) and pam3CSK, and the TLR4 ligand, Gram-negative bacterium-derived lipopolysaccharide (LPS). CA arrested the growth of dermatitis-inducing Gram-positive and Gram-negative microorganisms such Propionibacterium acnes, Pseudomonas aeruginosa, and Staphylococcus aureus. CA also blocked the nuclear translocation of nuclear factor (NF)-κB and its upstream signaling including Syk/Src, phosphoinositide 3-kinase (PI3K), Akt, inhibitor of κBα (IκBα) kinase (IKK), and IκBα for NF-κB activation. Kinase assays revealed that Syk could be direct enzymatic target of CA in its anti-inflammatory action. Therefore, our data strongly suggest the potential of CA as an anti-inflammatory drug against skin inflammatory responses with Src/NF-κB inhibitory properties.

Carnosic acid attenuates obesity‐induced glucose intolerance and hepatic fat accumulation by modulating genes of lipid metabolism in C57BL/6J‐ob/ob mice

“…Although the exact mechanism of CA on excess cytokine release in obesity is not fully understood, CA has been shown to inhibit NF‐ κ B activation. In keratinocyte HaCat cells, CA suppressed NF‐ κ B activation by blocking its upstream signals including Syk/Src, phosphoinositide 3‐kinase (PI3K), Akt, inhibitor of κ B α (I κ B α ) kinase (IKK) and I κ B α . CA induced apoptosis of human prostate carcinoma cells through the activation of serine/threonine protein phosphatase 2A (PP2A) by modulating the Akt/IKK/NF‐ κ B pathway .…”

Nrf2/ARE-mediated antioxidant actions of pro-electrophilic drugs

“…CA manifests significant protective effects in a cerebral artery occlusion model in mice (10), ameliorates obesity and hepatic steatosis in ob/ob mice [88, 89], inhibits microglial activation by lipopolysaccharide [90], inhibits adipocyte differentiation of 3T3-L1 cells [42], and abates light-induced retinal degeneration in rats [91]. In addition, CA and CS have been reported to display beneficial effects against acute and chronic inflammation, cardiovascular diseases, obesity, and cancer [94, 95], inhibition of prostaglandin synthesis [96], skin inflammation [97], p38 protein kinase activation [98], antiangiogenesis [99], protection against cisplatin [100], induction of neurotrophins [101], protection in an Alzheimer’s disease model [102], inhibition of NF-κB [103], inhibition of 5-lipoxygenase [104] and protection against dieldrin-induced degeneration of dopaminergic neurons [105]. For these reasons, we expect there to be intense activity in the coming years in an attempt to move these compounds or similar agents into clinical trials of specific patient populations, particularly for the CNS.…”

Src and Syk are targeted to an anti-inflammatory ethanol extract of Aralia continentalis

“…Although Ac-EE can strongly suppress Src and Syk, it is not yet clear which compounds act as active components in this extract. Recently, we found that CA is able to block both Src and Syk (Oh et al, 2012). Based on an HPLC finger printing assay, this extract was demonstrated to have similar types of diterpene compounds.…”