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. 2018 Oct 17:9:1181.
doi: 10.3389/fphar.2018.01181. eCollection 2018.

Curcumin's Metabolites, Tetrahydrocurcumin and Octahydrocurcumin, Possess Superior Anti-inflammatory Effects in vivo Through Suppression of TAK1-NF-κB Pathway

Zhen-Biao Zhang  1   2 , Dan-Dan Luo  1 , Jian-Hui Xie  3 , Yan-Fang Xian  2 , Zheng-Quan Lai  2   4 , Yu-Hong Liu  1 , Wei-Hai Liu  5 , Jian-Nan Chen  6 , Xiao-Ping Lai  1   7 , Zhi-Xiu Lin  1   2 , Zi-Ren Su  1   7
Affiliations

Curcumin's Metabolites, Tetrahydrocurcumin and Octahydrocurcumin, Possess Superior Anti-inflammatory Effects in vivo Through Suppression of TAK1-NF-κB Pathway

Zhen-Biao Zhang et al. Front Pharmacol. .

Abstract

Curcumin (CUR), a promising naturally occurring dietary compound, is commonly recognized as the potential anti-inflammatory agent. While the application of CUR was hampered by its low stability and poor systemic bioavailability, it has been suggested that the biological activities of CUR are intimately related to its metabolites. In the current investigation, we aimed to comparatively explore the anti-inflammatory effects of tetrahydrocurcumin (THC), octahydrocurcumin (OHC), and CUR, and to elucidate the underlying action mechanisms on experimental mice models of acute inflammation, i.e., xylene-induced ear edema, acetic acid-induced vascular permeability, and carrageenan-induced paw edema. The results showed that THC and OHC exerted significant and dose-dependent inhibitions on the formation of ear edema induced by xylene and paw edema provoked by carrageenan and inhibited the Evans blue dye leakage in peritoneal cavity elicited by acetic acid. Moreover, THC and OHC treatments were more effective than CUR in selectively inhibiting the expression of cyclooxygenase 2 (COX-2) and suppressing nuclear factor-κB (NF-κB) pathways via transforming growth factor β activated kinase-1 (TAK1) inactivation in the carrageenan-induced mouse paw edema model.

Keywords: COX-2; TAK1-NF-κB pathway; curcumin; inflammation; octahydrocucumin; tetrahydrocurcumin.

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Figures

FIGURE 1
FIGURE 1
Chemical structures of curcumin (CUR), tetrahydrocurcumin (THC), and octahydrocucumin (OHC).
FIGURE 2
FIGURE 2
Effects of THC and OHC on the xylene-induced ear edema in mice (A) and acetic acid-induced vascular permeability in mice (B). (A) The ear edema was assessed as the weight difference between the left and the right ear biopsies of the same animal. (B) The capillary permeability was represented as the amount of Evans blue extruded into peritoneal cavity, which was measured by the OD of the supernatant. Data were expressed as means ± S.E.M. (n = 10), ∗p < 0.05, ∗∗p < 0.01, ∗∗∗p < 0.001 vs. the vehicle control. Significant differences between groups were determined by ANOVA and Dunnett’s post hoc test.
FIGURE 3
FIGURE 3
Effects of THC and OHC on the carrageenan-induced paw edema in mice. (A) Paw edema degree was measured using the toes swelling measuring instrument and was represented as the mean ± S.E.M. (n = 10). (B) Suppression of paw edema (%) was calculated as the ratio of the mean paw size increase of THC and OHC treatment groups (%) over the vehicle control group (%).vs. the vehicle control. Significant differences between groups were determined by ANOVA and Dunnett’s post hoc test. Data were expressed as means ± S.E.M. (n = 10), ∗p < 0.05, ∗∗p < 0.01, ∗∗∗p < 0.001 vs the vehicle control.
FIGURE 4
FIGURE 4
Effects of THC and OHC on the levels of IL-1β (A), IL-6 (B), TNF-α (C), and PGE2 (D) in the carrageenan-induced mouse paw edema. After administration with THC (40 mg/kg, i.g.), OHC (40 mg/kg, i.g.) or CUR (100 mg/kg, i.g.) for 7 days, the hind paws were removed and placed in cold PBS (1:9, v/w). After homogenization and centrifugation, the resulting supernatants were collected and analyzed by ELISA kits. Data were expressed as means ± S.E.M. (n = 10), ###p < 0.001 vs. the intact control; ∗∗∗p < 0.001 vs. the vehicle control; formula imagep < 0.001 vs. the CUR group. Significant differences between groups were determined by ANOVA and Dunnett’s post hoc test.
FIGURE 5
FIGURE 5
Effects of THC and OHC on the mRNA (A,B) and protein (C,D) expressions of COX-1 and COX-2 in the carrageenan-induced mouse paw edema. After administration with THC (40 mg/kg, i.g.), OHC (40 mg/kg, i.g.) or CUR (100 mg/kg, i.g.) for 7 days, the hind paws were removed and isolated with TRIzol Reagent for analysis of mRNA expression of COX-1 and COX-2. Other hind paws were removed and homogenized in the lysis buffer, and then the protein extracts of hind paws were transferred to polyvinyl difluoride (PVDF) membranes and analyzed by Western blot. β-Actin was employed as the control for PCR. GAPDH was employed as loading control for Western blot. Data were expressed as means ± S.E.M. (n = 3), #p < 0.05, ###p < 0.001 vs. the intact control; ∗∗∗p < 0.001 vs. the vehicle control; formula imagep < 0.001 vs. the CUR group. Significant differences between groups were determined by ANOVA and Dunnett’s post hoc test.
FIGURE 6
FIGURE 6
Effects of (A) Representative lanes of TAB1, p-TAK1, and TAK1. THC and OHC on TAB1 (B), p-TAK1 (C), and TAK1 (D) protein expressions in the carrageenan-induced mouse paw edema. After administration with THC (40 mg/kg, i.g.), OHC (40 mg/kg, i.g.) or CUR (100 mg/kg, i.g.) for 7 days, the hind paws were removed and homogenized in the lysis buffer, and then the protein extracts of hind paws were transferred to polyvinyl difluoride (PVDF) membranes and analyzed by Western blot. GAPDH was employed as loading control. Data were expressed as means ± S.E.M. (n = 3), ###p < 0.001 vs. the intact control; ∗∗∗p < 0.001 vs. the vehicle control; formula imagep < 0.001 vs. the CUR group. Significant differences between groups were determined by ANOVA and Dunnett’s post hoc test.
FIGURE 7
FIGURE 7
Effects of (A) Representative lanes of IKKβ, p-IKKβ, IκBα, p-IκBα and p65 (cytosol). THC and OHC on IKKβ (B), p-IKKβ (C), IκBα (D), p-IκBα (E), and p65 (cytosol) (F) protein expressions in the carrageenan-induced mouse paw edema. After administration with THC (40 mg/kg, i.g.), OHC (40 mg/kg, i.g.) or CUR (100 mg/kg, i.g.) for 7 days, the hind paws were removed and homogenized in the lysis buffer, and then the protein extracts of hind paws were transferred to polyvinyl difluoride (PVDF) membranes and analyzed by Western blot. GAPDH was employed as loading control. Data were expressed as means ± S.E.M. (n = 3), ###p < 0.001 vs. the intact control; ∗∗∗p < 0.001 vs. the vehicle control; formula imagep < 0.001 vs. the CUR group. Significant differences between groups were determined by ANOVA and Dunnett’s post hoc test.
FIGURE 8
FIGURE 8
Effects of THC and OHC on p65 (nucleus) protein expression in the carrageenan-induced mouse paw edema. After administration with THC (40 mg/kg, i.g.), OHC (40 mg/kg, i.g.) or CUR (100 mg/kg, i.g.) for 7 days, the hind paws were removed and homogenized in the lysis buffer, and then the protein extracts of hind paws were transferred to PVDF membranes and analyzed by Western blot. Histone H3 was employed as loading control. Data were expressed as means ± S.E.M. (n = 3), ###p < 0.001 vs. the intact control; ∗∗∗p < 0.001 vs. the vehicle control. Significant differences between groups were determined by ANOVA and Dunnett’s post hoc test.
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