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Resveratrol as a Bioenhancer to Improve Anti-Inflammatory Activities of Apigenin.

Lee JA, Ha SK, Cho E, Choi I - Nutrients (2015)

Bottom Line: Co-administration of apigenin (50 mg/kg) and resveratrol (25 mg/kg) also showed a significant reduction of carrageenan-induced paw edema in mice (61.20% to 23.81%).Co-administration of apigenin and resveratrol led to a 2.39 fold increase in plasma apigenin levels compared to administration of apigenin alone, suggesting that co-administration of resveratrol could increase bioavailability of apigenin.These results suggested that resveratrol helps apigenin to bypass hepatic metabolism and maintain apigenin's anti-inflammatory activities in the body.

View Article: PubMed Central - PubMed

Affiliation: Research Group of Nutraceuticals for Metabolic Syndrome, Korea Food Research Institute, 1201-62, Anyangpangyoro, Seongnam, Gyeonggi 463-746, Korea. 07636@kfri.re.kr.

ABSTRACT
The aim of this study was to improve the anti-inflammatory activities of apigenin through co-treatment with resveratrol as a bioenhancer of apigenin. RAW 264.7 cells pretreated with hepatic metabolites formed by the co-metabolism of apigenin and resveratrol (ARMs) in HepG2 cells were stimulated with lipopolysaccharide (LPS). ARMs prominently inhibited (p < 0.05) the production of nitric oxide (NO), prostaglandin E₂ (PGE₂), interleukin (IL)-1β, IL-6 and TNF-α. Otherwise no such activity was observed by hepatic metabolites of apigenin alone (AMs). ARMs also effectively suppressed protein expressions of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Co-administration of apigenin (50 mg/kg) and resveratrol (25 mg/kg) also showed a significant reduction of carrageenan-induced paw edema in mice (61.20% to 23.81%). Co-administration of apigenin and resveratrol led to a 2.39 fold increase in plasma apigenin levels compared to administration of apigenin alone, suggesting that co-administration of resveratrol could increase bioavailability of apigenin. When the action of resveratrol on the main apigenin metabolizing enzymes, UDP-glucuronosyltransferases (UGTs), was investigated, resveratrol mainly inhibited the formation of apigenin glucuronides by UGT1A9 in a non-competitive manner with a Ki value of 7.782 μM. These results suggested that resveratrol helps apigenin to bypass hepatic metabolism and maintain apigenin's anti-inflammatory activities in the body.

No MeSH data available.


Related in: MedlinePlus

Effects of ARMs on LPS-stimulated IL-1β, IL-6 and TNF-α production in RAW 264.7 cells. The samples of hepatic metabolites were made as described in the Materials and Methods section. Cells were treated with the standard concentration (A; 20 μM) and hepatic metabolites of apigenin (AMs; 20 μM), hepatic metabolites of apigenin (20 μM) and resveratrol (10, 20 and 40 μM) (ARMs 1:0.5, 1:1 and 1:2), and hepatic metabolites of resveratrol (40 μM) for 30 min, and then incubated in the presence of LPS (1 μg/mL) for 18 h. The concentration of (A) IL-1β, (B) IL-6 and (C) TNF-α in the cell culture supernatants were measured as described in the Materials and Methods section. Data were presented as means ± SEM and were representative of triplicate experiments: *p < 0.05 compared to cells cultured with LPS (1 μg/mL) alone; # p < 0.05 compared to cells cultured with LPS (1 μg/mL) and AMs.
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nutrients-07-05485-f003: Effects of ARMs on LPS-stimulated IL-1β, IL-6 and TNF-α production in RAW 264.7 cells. The samples of hepatic metabolites were made as described in the Materials and Methods section. Cells were treated with the standard concentration (A; 20 μM) and hepatic metabolites of apigenin (AMs; 20 μM), hepatic metabolites of apigenin (20 μM) and resveratrol (10, 20 and 40 μM) (ARMs 1:0.5, 1:1 and 1:2), and hepatic metabolites of resveratrol (40 μM) for 30 min, and then incubated in the presence of LPS (1 μg/mL) for 18 h. The concentration of (A) IL-1β, (B) IL-6 and (C) TNF-α in the cell culture supernatants were measured as described in the Materials and Methods section. Data were presented as means ± SEM and were representative of triplicate experiments: *p < 0.05 compared to cells cultured with LPS (1 μg/mL) alone; # p < 0.05 compared to cells cultured with LPS (1 μg/mL) and AMs.

Mentions: Changes in the supernatant of IL-1β, IL-6 and TNF-α by pretreatments of A, AMs, ARMs, and RMs were measured (Figure 3). As expected, A inhibited the production of IL-1β (14.587 ± 0.636 pg/mL), IL-6 (2.343 ± 0.143 ng/mL) and TNF-α (8.149 ± 0.358 ng/mL) effectively (p < 0.05 compared to LPS alone) while AMs did not (236.901 ± 5.386 pg/mL, 61.947 ± 2.562 ng/mL and 27.411 ± 1.272 ng/mL, respectively). RMs also did not inhibit the production of these pro-inflammatory cytokines. ARMs, however, significantly inhibited the production of IL-1β (209.309 ± 12.121 pg/mL to 132.104 ± 1.691 pg/mL; p < 0.05 compared to LPS and AMs), IL-6 (52.668 ± 3.173 ng/mL to 22.458 ± 0.554 ng/mL; p < 0.05 compared to LPS and AMs) and TNF-α (28.790 ± 1.247 ng/mL to 23.628 ± 1.130 ng/mL; p < 0.05 compared to LPS and AMs) in the different concentrations of resveratrol. ARMs were more effective than AMs on suppressing the production of these pro-inflammatory cytokines.


Resveratrol as a Bioenhancer to Improve Anti-Inflammatory Activities of Apigenin.

Lee JA, Ha SK, Cho E, Choi I - Nutrients (2015)

Effects of ARMs on LPS-stimulated IL-1β, IL-6 and TNF-α production in RAW 264.7 cells. The samples of hepatic metabolites were made as described in the Materials and Methods section. Cells were treated with the standard concentration (A; 20 μM) and hepatic metabolites of apigenin (AMs; 20 μM), hepatic metabolites of apigenin (20 μM) and resveratrol (10, 20 and 40 μM) (ARMs 1:0.5, 1:1 and 1:2), and hepatic metabolites of resveratrol (40 μM) for 30 min, and then incubated in the presence of LPS (1 μg/mL) for 18 h. The concentration of (A) IL-1β, (B) IL-6 and (C) TNF-α in the cell culture supernatants were measured as described in the Materials and Methods section. Data were presented as means ± SEM and were representative of triplicate experiments: *p < 0.05 compared to cells cultured with LPS (1 μg/mL) alone; # p < 0.05 compared to cells cultured with LPS (1 μg/mL) and AMs.
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Related In: Results  -  Collection

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Show All Figures
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nutrients-07-05485-f003: Effects of ARMs on LPS-stimulated IL-1β, IL-6 and TNF-α production in RAW 264.7 cells. The samples of hepatic metabolites were made as described in the Materials and Methods section. Cells were treated with the standard concentration (A; 20 μM) and hepatic metabolites of apigenin (AMs; 20 μM), hepatic metabolites of apigenin (20 μM) and resveratrol (10, 20 and 40 μM) (ARMs 1:0.5, 1:1 and 1:2), and hepatic metabolites of resveratrol (40 μM) for 30 min, and then incubated in the presence of LPS (1 μg/mL) for 18 h. The concentration of (A) IL-1β, (B) IL-6 and (C) TNF-α in the cell culture supernatants were measured as described in the Materials and Methods section. Data were presented as means ± SEM and were representative of triplicate experiments: *p < 0.05 compared to cells cultured with LPS (1 μg/mL) alone; # p < 0.05 compared to cells cultured with LPS (1 μg/mL) and AMs.
Mentions: Changes in the supernatant of IL-1β, IL-6 and TNF-α by pretreatments of A, AMs, ARMs, and RMs were measured (Figure 3). As expected, A inhibited the production of IL-1β (14.587 ± 0.636 pg/mL), IL-6 (2.343 ± 0.143 ng/mL) and TNF-α (8.149 ± 0.358 ng/mL) effectively (p < 0.05 compared to LPS alone) while AMs did not (236.901 ± 5.386 pg/mL, 61.947 ± 2.562 ng/mL and 27.411 ± 1.272 ng/mL, respectively). RMs also did not inhibit the production of these pro-inflammatory cytokines. ARMs, however, significantly inhibited the production of IL-1β (209.309 ± 12.121 pg/mL to 132.104 ± 1.691 pg/mL; p < 0.05 compared to LPS and AMs), IL-6 (52.668 ± 3.173 ng/mL to 22.458 ± 0.554 ng/mL; p < 0.05 compared to LPS and AMs) and TNF-α (28.790 ± 1.247 ng/mL to 23.628 ± 1.130 ng/mL; p < 0.05 compared to LPS and AMs) in the different concentrations of resveratrol. ARMs were more effective than AMs on suppressing the production of these pro-inflammatory cytokines.

Bottom Line: Co-administration of apigenin (50 mg/kg) and resveratrol (25 mg/kg) also showed a significant reduction of carrageenan-induced paw edema in mice (61.20% to 23.81%).Co-administration of apigenin and resveratrol led to a 2.39 fold increase in plasma apigenin levels compared to administration of apigenin alone, suggesting that co-administration of resveratrol could increase bioavailability of apigenin.These results suggested that resveratrol helps apigenin to bypass hepatic metabolism and maintain apigenin's anti-inflammatory activities in the body.

View Article: PubMed Central - PubMed

Affiliation: Research Group of Nutraceuticals for Metabolic Syndrome, Korea Food Research Institute, 1201-62, Anyangpangyoro, Seongnam, Gyeonggi 463-746, Korea. 07636@kfri.re.kr.

ABSTRACT
The aim of this study was to improve the anti-inflammatory activities of apigenin through co-treatment with resveratrol as a bioenhancer of apigenin. RAW 264.7 cells pretreated with hepatic metabolites formed by the co-metabolism of apigenin and resveratrol (ARMs) in HepG2 cells were stimulated with lipopolysaccharide (LPS). ARMs prominently inhibited (p < 0.05) the production of nitric oxide (NO), prostaglandin E₂ (PGE₂), interleukin (IL)-1β, IL-6 and TNF-α. Otherwise no such activity was observed by hepatic metabolites of apigenin alone (AMs). ARMs also effectively suppressed protein expressions of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Co-administration of apigenin (50 mg/kg) and resveratrol (25 mg/kg) also showed a significant reduction of carrageenan-induced paw edema in mice (61.20% to 23.81%). Co-administration of apigenin and resveratrol led to a 2.39 fold increase in plasma apigenin levels compared to administration of apigenin alone, suggesting that co-administration of resveratrol could increase bioavailability of apigenin. When the action of resveratrol on the main apigenin metabolizing enzymes, UDP-glucuronosyltransferases (UGTs), was investigated, resveratrol mainly inhibited the formation of apigenin glucuronides by UGT1A9 in a non-competitive manner with a Ki value of 7.782 μM. These results suggested that resveratrol helps apigenin to bypass hepatic metabolism and maintain apigenin's anti-inflammatory activities in the body.

No MeSH data available.


Related in: MedlinePlus