Inhibitory effect of 3-caffeoyl-4-dicaffeoylquinic acid from Salicornia herbacea against phorbol ester-induced cyclooxygenase-2 expression in macrophages.

Salicornia herbacea (S. herbacea), an annual herb that grows in the salt marshes of the Korean peninsula, has been used as a folk medicine to treat a variety of diseases such as constipation, obesity, diabetes, and cancer. However, the effect of S. herbacea on inflammation is unclear. In the present study, we investigated the effects of a novel chlorogenic acid, 3-caffeoyl-4-dicaffeoylquinic acid (CDCQ), isolated from S. herbacea, on cyclooxygenase-2 (COX-2) expression in murine macrophage RAW 264.7 cells. Phorbol 12-myristate 13-acetate (PMA) induces COX-2 expression and production of prostaglandin E(2) (PGE(2)). PMA-induced COX-2 protein, gene expression and PGE(2) production were significantly inhibited by CDCQ in a dose-dependent manner. Transfection of hCOX-2, as well as of deletion and mutation promoter constructs, revealed that the CCAAT/enhancer-binding protein (C/EBP) and activator protein-1 (AP-1) predominantly contributed to the effects of CDCQ. In addition, electrophoretic mobility shift assays and transfection results showed that CDCQ directly inhibited PMA-induced C/EBP and AP-1 transcription and binding activity. CDCQ also remarkably reduced PMA-induced C/EBPbeta and c-jun protein expression. Furthermore, CDCQ significantly inhibited PMA-induced activation of the mitogen-activated protein kinases (MAP kinases), JNK and p38. These findings demonstrate that CDCQ effectively attenuates COX-2 production, and enhance our understanding of the anti-inflammatory properties of CDCQ.

Han EH ，Kim JY ，Kim HG ，Chun HK ，Chung YC ，Jeong HG ... -  《-》

3-Caffeoyl, 4-dihydrocaffeoylquinic acid from Salicornia herbacea inhibits tumor cell invasion by regulating protein kinase C-delta-dependent matrix metalloproteinase-9 expression.

In this study, we determined the effects of a novel chlorogenic acid, 3-caffeoyl, 4-dicaffeoylquinic acid (CDCQ) isolated from Salicornia herbacea, on tumor invasion and migration in human fibrosarcoma HT-1080 cells and investigated the possible mechanism(s) involved. CDCQ reduced the phorbol myristate acetate (PMA)-induced activation of matrix metalloproteinase (MMP)-9 and MMP-2 and inhibited cell invasion and migration. CDCQ suppressed PMA-induced expression of MMP-9 mRNA and protein by suppressing the transcription factor AP-1, without changing the level of tissue inhibitor of metalloproteinase (TIMP)-1. CDCQ-inhibited PMA-induced MMP-2 expression by suppressing membrane-type 1 MMP (MT1-MMP), but did not alter the TIMP-2 level. CDCQ also inhibited the PMA-induced nuclear translocation of c-Jun and c-Fos, which are upstream of PMA-induced MMP-9 expression. Furthermore, CDCQ strongly repressed PMA-induced phosphorylation of ERK, p38 MAPK, and JNK, which are dependent on the PKCdelta pathway. In conclusion, we demonstrated that the anti-invasive effects of CDCQ occur through the inhibition of AP-1 and signaling pathways involving PKCdelta and three MAPKs, leading to the downregulation of MMP-9 expression. Thus, CDCQ is an effective anti-metastatic agent that functions by downregulating MMP-9 gene expression.

Hwang YP ，Yun HJ ，Choi JH ，Chun HK ，Chung YC ，Kim SK ，Kim BH ，Kwon KI ，Jeong TC ，Lee KY ，Jeong HG ... -  《-》

Dihydro-N-caffeoyltyramine down-regulates cyclooxygenase-2 expression by inhibiting the activities of C/EBP and AP-1 transcription factors.

Dihydro-N-caffeoyltyramine (DHCT), a novel phenolic amide isolated from the root bark of Lycium chinense Miller, has potent antioxidative activity and anti-fungal effects. In the present study, we investigated the effects of DHCT on phorbol 12-myristate 13-acetate (PMA)-induced pro-inflammatory protein cyclooxygenase (COX-2) expression in macrophages. Treatment with DHCT suppressed PMA-mediated induction of COX-2 mRNA and protein. PMA-inducible production of PGE2 was inhibited by DHCT in a dose-dependent manner. Transient transfections and electrophoretic mobility shift assays indicated that the inhibitory effects of DHCT were mediated via CCAAT/enhancer-binding protein (C/EBP) and activator protein 1 (AP-1). DHCT reduced PMA-induced C/EBPbeta protein expression and c-jun/c-fos gene and protein expression. Furthermore, DHCT significantly inhibited PMA-induced activation of the mitogen activated protein (MAP) kinases (ERK and JNK). Thus, DHCT is an effective agent to attenuate COX-2 production mediated by the transcription factors C/EBP and AP-1, and these results enhance our understanding of the anti-inflammatory and anti-cancer properties by DHCT.

Han EH ，Kim JY ，Kim HG ，Choi JH ，Im JH ，Woo ER ，Jeong HG ... -  《-》

Celecoxib inhibits phorbol ester-induced expression of COX-2 and activation of AP-1 and p38 MAP kinase in mouse skin.

Chun KS ，Kim SH ，Song YS ，Surh YJ ... -  《CARCINOGENESIS》

Piperine inhibits PMA-induced cyclooxygenase-2 expression through downregulating NF-κB, C/EBP and AP-1 signaling pathways in murine macrophages.

Piperine is a major component of black (Piper nigrum Linn) and long (Piper longum Linn) peppers, and is widely used as a traditional food and medicine. It also exhibits a variety of biological activities, which include antioxidant, anti-tumor and anti-pyretic properties. In the present study, we investigated the inhibitory effects of piperine on phorbol 12-myristate 13-acetate (PMA)-induced cyclooxygenase-2 (COX-2) gene expression and analyzed the molecular mechanism of its activity in murine RAW 264.7 macrophages. Piperine dose-dependently decreased PMA-induced COX-2 expression and PGE(2) production, as well as COX-2 promoter-driven luciferase activity. Transient transfections utilizing COX-2 promoter deletion constructs and COX-2 promoter constructs, in which specific enhancer elements were mutagenized, revealed that the nuclear factor-κB (NF-κB), CCAAT/enhancer binding protein (C/EBP) and activator protein-1 (AP-1), were the predominant contributors to the effects of piperine. In addition, piperine inhibited PMA-induced NF-κB, C/EBP and c-Jun nuclear translocation. Furthermore, piperine significantly inhibited PMA-induced activation of the Akt and ERK. These findings demonstrate that piperine effectively attenuates COX-2 production, and provide further insight into the signal transduction pathways involved in the anti-inflammatory effects of piperine.

Kim HG ，Han EH ，Jang WS ，Choi JH ，Khanal T ，Park BH ，Tran TP ，Chung YC ，Jeong HG ... -  《-》