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Rotundarpene inhibits TNF-α-induced activation of the Akt, mTOR, and NF-κB pathways, and the JNK and p38 associated with production of reactive oxygen species

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Abstract

Ilex Rotunda Thunb has been shown to have anti-inflammatory and antioxidant effects. In human keratinocytes, we investigated the effect of rotundarpene (4-caffeoyl-3-methyl-but-2-ene-1,4-diol) on the TNF-α-stimulated production of inflammatory mediators in relation to the Akt, mTOR, and NF-κB pathways, and the JNK and p38-MAPK. Rotundarpene, Akt inhibitor, Bay 11-7085, rapamycin, and N-acetylcysteine inhibited the TNF-α-stimulated production of cytokines and chemokines, increase in the levels of p-Akt and mTOR, activation of NF-κB, and production of reactive oxygen species in keratinocytes. TNF-α treatment induced phosphorylation of the JNK and p38-MAPK. Inhibitors of the c-JNK (SP600125) and p38-MAPK (SB203580) reduced the TNF-α-induced production of inflammatory mediators, binding of NF-κB to DNA, and activation of the JNK and p38-MAPK in keratinocytes. The results show that rotundarpene may reduce the TNF-α-stimulated inflammatory mediator production by suppressing the reactive oxygen species-dependent activation of the Akt, mTOR, and NF-κB pathways, and activation of the JNK and p38-MAPK in human keratinocytes. Additionally, rotundarpene appears to attenuate the Akt, mTOR, and NF-κB pathways and the JNK and p38-MAPK-mediated inflammatory skin diseases.

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Abbreviations

TNF-α:

Tumor necrosis factor-α

PI3K:

Phosphatidylinositol-4,5-bisphosphate 3-kinase

mTOR:

Mammalian target of rapamycin

NF-κB:

Nuclear factor-κB

MAPKs:

Mitogen-activated protein kinases

ERKs:

Extracellular signal-regulated kinases

JNKs:

c-Jun NH2-terminal kinases

p38-MAPK:

p38-Mitogen-activated protein kinase

EGF:

Epidermal growth factor

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Correspondence to Chung Soo Lee.

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Kim, A., Nam, Y.J., Shin, Y.K. et al. Rotundarpene inhibits TNF-α-induced activation of the Akt, mTOR, and NF-κB pathways, and the JNK and p38 associated with production of reactive oxygen species. Mol Cell Biochem 434, 113–125 (2017). https://doi.org/10.1007/s11010-017-3041-x

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