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Aberrant expression of matrix metalloproteinase-9 (MMP-9) is implicated in the process of invasion and angiogenesis of malignant tumors as well as in inflammatory diseases of the CNS. Therefore, the development of compounds that can inhibit or suppress MMP-9 is required to treat brain tumors. We investigated the effects of a ginseng saponin metabolite, compound K (20-O-(b-D-glucopyranosyl)-20(S)-protopanaxadiol), on MMP-9 expression in human astroglioma cells. Compound K significantly inhibited the secretion and protein expression of MMP-9 induced by PMA. The inhibitory effect of compound K on MMP-9 expression correlated with decreased MMP-9 mRNA levels and suppression of MMP-9 promoter activity. The compound K-mediated inhibition of MMP-9 gene expression appears to occur via AP-1 because its DNA-binding and transcriptional activities were suppressed by the agent. Furthermore, compound K significantly repressed the PMA-mediated activation of p38 MAPK, ERK and JNK, which are upstream modulators of AP-1. Finally, compound K inhibited the in vitro invasiveness of glioma cells. Therefore, inhibition of MMP-9 expression by compound K might have therapeutic potential for controlling the growth and invasiveness of brain tumors. ' 2005 Wiley-Liss, Inc.Key words: compound K; astroglioma; matrix metalloproteinase-9; activator protein-1; mitogen-activated protein kinase Glioma is the most common primary brain tumor in adults. Despite the many treatments, including surgery, chemotherapy and radiation therapy, glioma is one of the most lethal malignancies, with a median survival of <2 years.1 Cancer gene therapy for the treatment of brain tumors by targeting the prodrug/suicidal genes, tumor-suppressor genes, immune-enhancing cytokine genes and angiogenesis-related genes has attracted a great deal of attention.2 In particular, the specific inhibition of tumor angiogenesis, which is the formation of a blood vessel network within a tumor, is considered to have the most potential as a therapeutic target in cancer medicine. 3MMPs are mainly implicated in the degradation of ECM macromolecules, which are important for creating the cellular environment during development and morphogenesis. In pathologic circumstances, such as cancer, arthritis and various inflammatory conditions, improper regulation of these molecules contributes to their pathogenesis.4,5 Therefore, MMPs play an important role in the remodeling of the ECM as well as in a variety of physiologic and pathologic processes, including embryonic growth and development, migration of blood leukocytes into tissues, tumor invasion, metastasis and angiogenesis. MMPs consist of 4 groups according to their substrates, which include collagenases, gelatinases, stromelysins and membraneassociated MMPs. Among them, gelatinase-B (MMP-9) has been reported to be a key enzyme for degrading type IV collagen, which is a major component of the basement membrane; and elevated MMP-9 levels have been found in patients suffering from various types of tumor in vivo. 7,8 In addition, MMP-9 over...

The microglial activation plays an important role in neurodegenerative diseases by producing several proinflammatory cytokines and nitric oxide (NO). We found that three types of isoflavones and their metabolites that are transformed by the human intestinal microflora suppress lipopolysaccharide (LPS)-induced release of NO and tumor necrosis factor (TNF)-␣ in primary cultured microglia and BV2 microglial cell lines. The inhibitory effect of the isoflavone metabolites (aglycon form) was more potent than that of isoflavones (glycoside form). The RNase protection assay showed that the isoflavone metabolites regulated inducible nitric oxide synthase (iNOS) and the cytokines at either the transcriptional or post-transcriptional level. A further molecular mechanism study was performed for irisolidone, a metabolite of kakkalide, which had the most potent anti-inflammatory effect among the six isoflavones tested.Irisolidone significantly inhibited the DNA binding and transcriptional activity of nuclear factor (NF)-B and activator protein-1. Moreover, it repressed the LPS-induced extracellular signalregulated kinase (ERK) phosphorylation without affecting the activity of c-Jun N-terminal kinase or p38 mitogen-activated protein kinase. The level of NF-B inhibition by irisolidone correlated with the level of iNOS, TNF-␣, and interleukin (IL)-1␤ suppression in LPS-stimulated microglia, whereas the level of ERK inhibition correlated with the level of TNF-␣ and IL-1␤ repression. Overall, the repression of proinflammatory cytokines and iNOS gene expression in activated microglia by isoflavones such as irisolidone might have therapeutic potential for various neurodegenerative diseases including ischemic cerebral disease.Microglia are the primary immune cells of the brain that are activated in response to brain injury and release of various neurotrophic factors supporting neuronal cell survival or neurotoxic factors, including nitric oxide (NO) and proinflammatory cytokines such as TNF-␣ and IL-1␤ (Kreutzberg, 1996). There is accumulating evidence suggesting that microglial activation is not just a single phenotype but is also a complex array of responses (Town et al., 2005). It was suggested that once activated, microglial cells exist in at least two functionally distinct states, namely a phagocytic phenotype (innate activation) or an antigen-presenting phenotype (adaptive activation), as determined by their stimulatory environment. The imbalance of these states can render microglial activation either beneficial or detrimental to neurons.A number of studies have reported that neuronal cell death causes microglial activation by releasing various signaling molecules (Aldskogius et al., 1999;Kim et al., 2005), which suggests that neuroinflammation is the result of an ongoing disease process. On the other hand, several studies have suggested that activated microglia play a role as a possible cause of Alzheimer's disease by secreting proinflammatory cytokines such as TNF-␣ and IL-1␤, which have been shown to promote neuronal...