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Abstract: Extensive research within the past half-century has indicated that curcumin (diferuloylmethane), a yellow pigment in curry powder, exhibits antioxidant, anti-inflammatory, and proapoptotic activities. We investigated whether the anti-inflammatory and proapoptotic activities assigned to curcumin are mediated through its prooxidant/antioxidant mechanism. We found that TNF-mediated NF-κB activation was inhibited by curcumin; and glutathione reversed the inhibition. Similarly, suppression of TNF-induced AKT activation by curcumin was also abrogated by glutathione. The reducing agent also counteracted the inhibitory effects of curcumin on TNF-induced NF-κB-regulated antiapoptotic (Bcl-2, Bcl-xL, IAP1), proliferative (cyclin D1), and proinflammatory (COX-2, iNOS, and MMP-9) gene products. The suppression of TNF-induced AP-1 activation by curcumin was also reversed by glutathione. Also, the direct proapoptotic effects of curcumin were inhibited by glutathione and potentiated by depletion of intracellular glutathione by buthionine sulfoximine. Moreover, curcumin induced the production of reactive oxygen species and modulated intracellular GSH levels. Quenchers of hydroxyl radicals, however, were ineffective in inhibiting curcumin-mediated NF-κB suppression. Further, N-acetylcysteine partially reversed the effect of curcumin. Based on these results we conclude that curcumin mediates its apoptotic and anti-inflammatory activities through modulation of the redox status of the cell. [Copyright &y& Elsevier]

Plumbagin, derived from the medicinal plant Plumbago zeylanica, modulates cellular proliferation, carcinogenesis, and radioresistance, all known to be regulated by the activation of the transcription factor NF-κB, suggesting plumbagin might affect the NF-κB activation pathway. We found that plumbagin inhibited NF-κB activation induced by TNF, and other carcinogens and inflammatory stimuli (e.g. phorbol 12-myristate 13-acetate, H2O2, cigarette smoke condensate, interleukin-1β, lipopolysaccharide, and okadaic acid). Plumbagin also suppressed the constitutive NF-κB activation in certain tumor cells. The suppression of NF-κB activation correlated with sequential inhibition of the tumor necrosis factor (TNF)-induced activation of IκBα kinase, lκBα phosphorylation, IκBα degradation, p65 phosphorylation, p65 nuclear translocation, and the NF-κB-dependent reporter gene expression activated by TNF, TNFR1, TRAF2, NIK, IKK-β, and the p65 subunit of NF-κB. Plumbagin also suppressed the direct binding of nuclear p65 and recombinant p65 to the DNA, and this binding was reversed by dithiothreitol both in vitro and in vivo. However, plumbagin did not inhibit p65 binding to DNA when cells were transfected with the p65 plasmid containing cysteine 38 mutated to serine. Plumbagin down-regulated the expression of NF-κB-regulated anti-apoptotic (IAP1, IAP2, Bcl-2, Bcl-xL, cFLIP, Bfl-1/A1, and survivin), proliferative (cyclin D1 and COX-2), and angiogenic (matrix metalloproteinase-9 and vascular endothelial growth factor) gene products. This led to potentiation of apoptosis induced by TNF and paclitaxel and inhibited cell invasion. Overall, our results indicate that plumbagin is a potent inhibitor of the NF-κB activation pathway that leads to suppression of NF-κB-regulated gene products. This may explain its cell growth modulatory, anticarcinogenic, and radiosensitizing effects previously described. [ABSTRACT FROM AUTHOR]

Traditional Chinese medicine (TCM) is an attractive model for studying antioxidant-based composite therapy. We previously reported that Shengmai San (SMS), a TCM formulation for treating cardiac disorders, inhibited cerebral oxidative damage in rats when evaluated by both glutathione peroxidase (GPX) activity loss and thiobarbituric acid reactive substance (TBARS) formation after forebrain ischemia-reperfusion. In the present study, we further examined the preventive effect of SMS and related decoctions composed of three component herbs (Panax ginseng, Ophiopogon japonicus and Schisandra chinensis) against oxidative brain injury to rationalize the complex formulation of SMS. Schisandra chinensis itself and decoctions containing it all inhibited TBARS formation in vivo. In contrast, Ophiopogon japonicus itself and formulations containing it had little effect on TBARS formation. GPX activity loss in vivo, on the other hand, was completely prevented only by SMS and Ophiopogon japonicus itself. A comparison of the in vitro antioxidant potential of SMS and related decoctions and in vivo effectiveness in preventing cerebral oxidative damage revealed that all the in vitro antioxidant indices examined here essentially correlated well with inhibition of TBARS formation in vivo. DPPH quenching and crocin bleaching activities showed particularly good correlation, and then, superoxide scavenging activity followed. However, none of them correlated with the inhibition of GPX activity loss in vivo. The role of each component herb is also discussed for the SMS effect. [ABSTRACT FROM AUTHOR]

Aim of the study: Lagerstroemia speciosa has been used as a folk medicine among people with diabetes in the Philippines. It is known to exhibit antidiabetic, antiobesity, and glucose transport activities through mechanisms not well defined. Diabetes leads to cardiomyocyte hypertrophy in association with an upregulation of vasoactive factors and activation of nuclear factor (NF)-κB and activating protein-1. We therefore investigated the effect of Lagerstroemia speciosa on the activation of NF-κB as a key mediator of cardiomyocyte hypertrophy, in rat cardiomyocyte H9c2 cells. Materials and methods: Water extract of Lagerstroemia speciosa (Lythraceae family) was prepared. H9c2 cells were used for treatment of Lagerstroemia speciosa extract with/without tumor necrosis factor (TNF). To examine NF-κB''s activation, we performed an electrophoretic mobility shift assay (EMSA). Results: The activation of NF-κB by TNF was completely blocked by a Lagerstroemia speciosa extract in a dose- and time-dependent manner in H9c2 cells. Conclusion: Overall, our results indicate that Lagerstroemia speciosa can inhibit DNA-binding of NF-κB. This may explain its possible inhibition of diabetes-induced caridomyocyte hypertrophy. [Copyright &y& Elsevier]

Zyflamend, a polyherbal preparation, was designed based on constituents that exhibit antiproliferative, antiinflammatory, antioxidant, antiangiogenic, and apoptotic activities through a mechanism that is not well defined. Because the nuclear factor (NF)-κB has been shown to regulate proliferation, invasion, and metastasis of tumor cells, we postulated that Zyflamend modulates the activity of NF-κ B. To test this hypothesis, we examined the effect of this preparation on NF-κB and NF-κB—regulated gene products. We found that Zyflamend inhibited receptor activator of NF-κ B ligand—induced osteoclastogenesis, suppressed tumor necrosis factor (TNF)-induced invasion, and potentiated the cytotoxicity induced by TNF and chemotherapeutic agents, all of which are known to require NF-κ B activation. Zyflamend suppressed NF-κ B activation induced by both TNF and cigarette smoke condensate. The expression of NF-κ B—regulated gene products involved in antiapoptosis (inhibitor-of-apoptosis protein 1/2, Bcl-2, Bcl-xL, FADD-like interleukin-1βconverting enzyme/caspase-8 inhibitory protein, TNF receptor-associated factor-1, and survivin) and angiogenesis (vascular endothelial growth factor, cyclooxygenase-2, intercellular adhesion molecule, and matrix metalloproteinase-9) was also down-regulated by Zyflamend. This correlated with potentiation of cell death induced by TNF and chemotherapeutic agents. Overall, our results indicate that Zyflamend suppresses osteoclastogenesis, inhibits invasion, and potentiates cytotoxicity through down-regulation of NF-κ B activation and NF-κ B—regulated gene products. [ABSTRACT FROM AUTHOR]

Because of its ability to suppress tumor cell proliferation, angiogenesis, and inflammation, the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) is currently in clinical trials. How SAHA mediates its effects is poorly understood. We found that in several human cancer cell lines, SAHA potentiated the apoptosis induced by tumor necrosis factor (TNF) and chemotherapeutic agents and inhibited TNF-induced invasion and receptor activator of NF-κB ligand-induced osteoclastogenesis, all of which are known to require NF-κB activation. These observations corresponded with the down-regulation of the expression of anti-apoptotic (IAP1, IAP2, X chromosome-linked IAP, Bcl-2, Bcl-xL, TRAF1, FLIP, and survivin), proliferative (cyclin D1, cyclooxygenase 2, and c-Myc), and angiogenic (ICAM-1, matrix metalloproteinase-9, and vascular endothelial growth factor) gene products. Because several of these genes are regulated by NF-κB, we postulated that SAHA mediates its effects by modulating NF-κB and found that SAHA suppressed NF-κB activation induced by TNF, IL-1β, okadaic acid, doxorubicin, lipopolysaccharide, H2O2, phorbol myristate acetate, and cigarette smoke; the suppression was not cell type-specific because both inducible and constitutive NF-κB activation was inhibited. We also found that SAHA had no effect on direct binding of NF-κB to the DNA but inhibited sequentially the TNF-induced activation of IκBα kinase, IκBα phosphorylation, IκBα ubiquitination, IκBα degradation, p65 phosphorylation, and p65 nuclear translocation. Furthermore, SAHA inhibited the NF-κB-dependent reporter gene expression activated by TNF, TNFR1, TRADD, TRAF2, NF-κB-inducing kinase, IκBα kinase, and the p65 subunit of NF-κB. Overall, our results indicated that NF-κB and NF-κB-regulated gene expression inhibited by SAHA can enhance apoptosis and inhibit invasion and osteoclastogenesis. [ABSTRACT FROM AUTHOR]

Recent evidence indicates a convergence of molecular targets for both prevention and therapy of cancer. Signal-transducer-and-activator-of-transcription-3 (STAT3), a member of a family of six different transcription factors, is closely linked with tumorigenesis. Its role in cancer is indicated by numerous avenues of evidence, including the following: STAT3 is constitutively active in tumor cells; STAT3 is activated by growth factors (e.g., EGF, TGF-α, IL-6, hepatocyte growth factor) and oncogenic kinases (e.g., Src); STAT3 regulates the expression of genes that mediate proliferation (e.g., c-myc and cyclin D1), suppress apoptosis (e.g., Bcl-xL and survivin), or promote angiogenesis (e.g, VEGF); STAT3 activation has been linked with chemoresistance and radioresistance; and chemopreventive agents have been shown to suppress STAT3 activation. Thus inhibitors of STAT3 activation have potential for both prevention and therapy of cancer. Besides small peptides and oligonucleotides, numerous small molecules have been identified as blockers of STAT3 activation, including synthetic molecules (e.g., AG 490, decoy peptides, and oligonucleotides) and plant polyphenols (e.g., curcumin, resveratrol, flavopiridol, indirubin, magnolol, piceatannol, parthenolide, EGCG, and cucurbitacin). This article discusses these aspects of STAT3 in more detail. [ABSTRACT FROM AUTHOR]