Limits...
Hyperforin, an Anti-Inflammatory Constituent from St. John's Wort, Inhibits Microsomal Prostaglandin E(2) Synthase-1 and Suppresses Prostaglandin E(2) Formation in vivo.

Koeberle A, Rossi A, Bauer J, Dehm F, Verotta L, Northoff H, Sautebin L, Werz O - Front Pharmacol (2011)

Bottom Line: The acylphloroglucinol hyperforin (Hyp) from St. John's wort possesses anti-inflammatory and anti-carcinogenic properties which were ascribed among others to the inhibition of 5-lipoxygenase.Intraperitoneal (i.p.) administration of Hyp (4 mg kg(-1)) to rats impaired exudate volume and leukocyte numbers in carrageenan-induced pleurisy associated with reduced PGE(2) levels, and Hyp (given i.p.) inhibited carrageenan-induced mouse paw edema formation (ED(50) = 1 mg kg(-1)) being superior over indomethacin (ED(50) = 5 mg kg(-1)).We conclude that the suppression of PGE(2) biosynthesis in vitro and in vivo by acting on mPGES-1 critically contributes to the anti-inflammatory efficiency of Hyp.

View Article: PubMed Central - PubMed

Affiliation: Department for Pharmaceutical Analytics, Pharmaceutical Institute, University of Tübingen Tübingen, Germany.

ABSTRACT
The acylphloroglucinol hyperforin (Hyp) from St. John's wort possesses anti-inflammatory and anti-carcinogenic properties which were ascribed among others to the inhibition of 5-lipoxygenase. Here, we investigated whether Hyp also interferes with prostanoid generation in biological systems, particularly with key enzymes participating in prostaglandin (PG)E(2) biosynthesis, i.e., cyclooxygenases (COX)-1/2 and microsomal PGE(2) synthase (mPGES)-1 which play key roles in inflammation and tumorigenesis. Similar to the mPGES-1 inhibitors MK-886 and MD-52, Hyp significantly suppressed PGE(2) formation in whole blood assays starting at 0.03-1 μM, whereas the concomitant generation of COX-derived 12(S)-hydroxy-5-cis-8,10-trans-heptadecatrienoic acid, thromboxane B(2), and 6-keto PGF(1α) was not significantly suppressed up to 30 μM. In cell-free assays, Hyp efficiently blocked the conversion of PGH(2) to PGE(2) mediated by mPGES-1 (IC(50) = 1 μM), and isolated COX enzymes were not (COX-2) or hardly (COX-1) suppressed. Intraperitoneal (i.p.) administration of Hyp (4 mg kg(-1)) to rats impaired exudate volume and leukocyte numbers in carrageenan-induced pleurisy associated with reduced PGE(2) levels, and Hyp (given i.p.) inhibited carrageenan-induced mouse paw edema formation (ED(50) = 1 mg kg(-1)) being superior over indomethacin (ED(50) = 5 mg kg(-1)). We conclude that the suppression of PGE(2) biosynthesis in vitro and in vivo by acting on mPGES-1 critically contributes to the anti-inflammatory efficiency of Hyp.

No MeSH data available.


Related in: MedlinePlus

Effects of hyperforin on apoptosis and the expression of COX-2 and mPGES-1. A549 cells, 60% confluent, were incubated with 2 ng ml−1 interleukin-1β together with vehicle (DMSO) or Hyp in cell culture medium containing 2% (v v−1) fetal calf serum. Cells were harvested after 24 h, total cell lysates were prepared and analyzed for the induction of COX-2 (72 kDa), mPGES-1 (16 kDa) and cleaved PARP (89 kDa) using SDS-PAGE and Western blotting. β-Actin (45 kDa) was used as loading control. Data are representatives of two to three independent experiments.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3108608&req=5

Figure 5: Effects of hyperforin on apoptosis and the expression of COX-2 and mPGES-1. A549 cells, 60% confluent, were incubated with 2 ng ml−1 interleukin-1β together with vehicle (DMSO) or Hyp in cell culture medium containing 2% (v v−1) fetal calf serum. Cells were harvested after 24 h, total cell lysates were prepared and analyzed for the induction of COX-2 (72 kDa), mPGES-1 (16 kDa) and cleaved PARP (89 kDa) using SDS-PAGE and Western blotting. β-Actin (45 kDa) was used as loading control. Data are representatives of two to three independent experiments.

Mentions: We investigated whether Hyp might suppress PGE2 formation by interfering with COX-2 or mPGES-1 expression during prolonged incubation times (24 h). In fact, Hyp concentration-dependently inhibited the induction of COX-2 and mPGES-1 with an EC50 of 1–3 μM in IL-1β-stimulated A549 cells (a model lung carcinoma cell line to study mPGES-1 functions), and also β-actin levels were slightly reduced at 10 μM (Figure 5). Since previous studies showed that Hyp causes apoptosis of various cancer cell lines (Schempp et al., 2002; Hostanska et al., 2003; Dona et al., 2004), we reasoned that reduced expression of COX-2 and mPGES-1 in A549 cells by Hyp may be related to induction of apoptotic cell death. In fact, the decrease of COX-2 and mPGES-1 protein correlated with the induction of apoptosis as determined by the cleavage of PARP (Figure 5), and the cell viability was strongly reduced after 24 h (EC50 ≈ 3 μM, not shown).


Hyperforin, an Anti-Inflammatory Constituent from St. John's Wort, Inhibits Microsomal Prostaglandin E(2) Synthase-1 and Suppresses Prostaglandin E(2) Formation in vivo.

Koeberle A, Rossi A, Bauer J, Dehm F, Verotta L, Northoff H, Sautebin L, Werz O - Front Pharmacol (2011)

Effects of hyperforin on apoptosis and the expression of COX-2 and mPGES-1. A549 cells, 60% confluent, were incubated with 2 ng ml−1 interleukin-1β together with vehicle (DMSO) or Hyp in cell culture medium containing 2% (v v−1) fetal calf serum. Cells were harvested after 24 h, total cell lysates were prepared and analyzed for the induction of COX-2 (72 kDa), mPGES-1 (16 kDa) and cleaved PARP (89 kDa) using SDS-PAGE and Western blotting. β-Actin (45 kDa) was used as loading control. Data are representatives of two to three independent experiments.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3108608&req=5

Figure 5: Effects of hyperforin on apoptosis and the expression of COX-2 and mPGES-1. A549 cells, 60% confluent, were incubated with 2 ng ml−1 interleukin-1β together with vehicle (DMSO) or Hyp in cell culture medium containing 2% (v v−1) fetal calf serum. Cells were harvested after 24 h, total cell lysates were prepared and analyzed for the induction of COX-2 (72 kDa), mPGES-1 (16 kDa) and cleaved PARP (89 kDa) using SDS-PAGE and Western blotting. β-Actin (45 kDa) was used as loading control. Data are representatives of two to three independent experiments.
Mentions: We investigated whether Hyp might suppress PGE2 formation by interfering with COX-2 or mPGES-1 expression during prolonged incubation times (24 h). In fact, Hyp concentration-dependently inhibited the induction of COX-2 and mPGES-1 with an EC50 of 1–3 μM in IL-1β-stimulated A549 cells (a model lung carcinoma cell line to study mPGES-1 functions), and also β-actin levels were slightly reduced at 10 μM (Figure 5). Since previous studies showed that Hyp causes apoptosis of various cancer cell lines (Schempp et al., 2002; Hostanska et al., 2003; Dona et al., 2004), we reasoned that reduced expression of COX-2 and mPGES-1 in A549 cells by Hyp may be related to induction of apoptotic cell death. In fact, the decrease of COX-2 and mPGES-1 protein correlated with the induction of apoptosis as determined by the cleavage of PARP (Figure 5), and the cell viability was strongly reduced after 24 h (EC50 ≈ 3 μM, not shown).

Bottom Line: The acylphloroglucinol hyperforin (Hyp) from St. John's wort possesses anti-inflammatory and anti-carcinogenic properties which were ascribed among others to the inhibition of 5-lipoxygenase.Intraperitoneal (i.p.) administration of Hyp (4 mg kg(-1)) to rats impaired exudate volume and leukocyte numbers in carrageenan-induced pleurisy associated with reduced PGE(2) levels, and Hyp (given i.p.) inhibited carrageenan-induced mouse paw edema formation (ED(50) = 1 mg kg(-1)) being superior over indomethacin (ED(50) = 5 mg kg(-1)).We conclude that the suppression of PGE(2) biosynthesis in vitro and in vivo by acting on mPGES-1 critically contributes to the anti-inflammatory efficiency of Hyp.

View Article: PubMed Central - PubMed

Affiliation: Department for Pharmaceutical Analytics, Pharmaceutical Institute, University of Tübingen Tübingen, Germany.

ABSTRACT
The acylphloroglucinol hyperforin (Hyp) from St. John's wort possesses anti-inflammatory and anti-carcinogenic properties which were ascribed among others to the inhibition of 5-lipoxygenase. Here, we investigated whether Hyp also interferes with prostanoid generation in biological systems, particularly with key enzymes participating in prostaglandin (PG)E(2) biosynthesis, i.e., cyclooxygenases (COX)-1/2 and microsomal PGE(2) synthase (mPGES)-1 which play key roles in inflammation and tumorigenesis. Similar to the mPGES-1 inhibitors MK-886 and MD-52, Hyp significantly suppressed PGE(2) formation in whole blood assays starting at 0.03-1 μM, whereas the concomitant generation of COX-derived 12(S)-hydroxy-5-cis-8,10-trans-heptadecatrienoic acid, thromboxane B(2), and 6-keto PGF(1α) was not significantly suppressed up to 30 μM. In cell-free assays, Hyp efficiently blocked the conversion of PGH(2) to PGE(2) mediated by mPGES-1 (IC(50) = 1 μM), and isolated COX enzymes were not (COX-2) or hardly (COX-1) suppressed. Intraperitoneal (i.p.) administration of Hyp (4 mg kg(-1)) to rats impaired exudate volume and leukocyte numbers in carrageenan-induced pleurisy associated with reduced PGE(2) levels, and Hyp (given i.p.) inhibited carrageenan-induced mouse paw edema formation (ED(50) = 1 mg kg(-1)) being superior over indomethacin (ED(50) = 5 mg kg(-1)). We conclude that the suppression of PGE(2) biosynthesis in vitro and in vivo by acting on mPGES-1 critically contributes to the anti-inflammatory efficiency of Hyp.

No MeSH data available.


Related in: MedlinePlus