Biomolecules & Therapeutics  https://doi.org/10.4062/biomolther.2022.039
6-Shogaol and 10-Shogaol Synergize Curcumin in Ameliorating Proinflammatory Mediators via the Modulation of TLR4/TRAF6/MAPK and NFκB Translocation
Xian Zhou1,*, Ahmad Al-Khazaleh1, Sualiha Afzal2, Ming-Hui (Tim) Kao2, Gerald Münch2, Hans Wohlmuth1,3,4, David Leach3, Mitchell Low1 and Chun Guang Li1,*
1NICM Health Research Institute, Western Sydney University, Westmead, NSW 2145,
2School of Medicine, Western Sydney University, Campbelltown, NSW 2560,
3Integria Healthcare, Building 5, Freeway Office Park, QLD 4113,
4School of Chemistry & Molecular Biosciences, The University of Queensland, St Lucia, QLD 4072, Australia
*E-mail: c.li@westernsydney.edu.au (Li CG), p.zhou@westernsydney.edu.au (Zhou X)
Tel: +61-2-9685-4743 (Li CG), +61-2-9685-4741 (Zhou X)
Fax: +61-2-9685-4760 (Li CG), +61-2-9685-4760 (Zhou X)
Received: March 15, 2022; Revised: August 11, 2022; Accepted: August 18, 2022; Published online: November 2, 2022.
© The Korean Society of Applied Pharmacology. All rights reserved.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
Extensive research supported the therapeutic potential of curcumin, a naturally occurring compound, as a promising cytokinesuppressive anti-inflammatory drug. This study aimed to investigate the synergistic anti-inflammatory and anti-cytokine activities by combining 6-shogaol and 10-shogaol to curcumin, and associated mechanisms in modulating lipopolysaccharides and interferon-ɣ-induced proinflammatory signaling pathways. Our results showed that the combination of 6-shogaol-10-shogaolcurcumin synergistically reduced the production of nitric oxide, inducible nitric oxide synthase, tumor necrosis factor and interlukin-6 in lipopolysaccharides and interferon-γ-induced RAW 264.7 and THP-1 cells assessed by the combination index model. 6-shogaol-10-shogaol-curcumin also showed greater inhibition of cytokine profiling compared to that of 6-shogaol-10-shogaol or curcumin alone. The synergistic anti-inflammatory activity was associated with supressed NFκB translocation and downregulated TLR4-TRAF6-MAPK signaling pathway. In addition, SC also inhibited microRNA-155 expression which may be relevant to the inhibited NFκB translocation. Although 6-shogaol-10-shogaol-curcumin synergistically increased Nrf2 activity, the anti-inflammatory mechanism appeared to be independent from the induction of Nrf2. 6-shogaol-10-shogaol-curcumin provides a more potent therapeutic agent than curcumin alone in synergistically inhibiting lipopolysaccharides and interferon-γ induced proinflammatory mediators and cytokine array in macrophages. The action was mediated by the downregulation of TLR4/TRAF6/MAPK pathway and NFκB translocation.
Keywords: Curcumin, Shogaol, Synergy, Anti-inflammatory, NFκB, TLR4/TRAF6/MAPK


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