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Andrographolides found in PARACTIN^® is a major active component from Andrographis paniculata, has shown to possess anti-inflammatory activity.  Andrographolides found in PARACTIN^® inhibits the expression of several pro-inflammatory proteins that share an element of NF- "Times New Roman";mso-char-type:symbol;mso-symbol-font-family:Symbol">kB in the gene.  Nuclear factor kappa B (NF-kB) is a transcription factor found in a great variety of immune cells that plays an important role in the inflammatory and immune response by regulating proinflammatory cytokines (interleukin-1, -2, -6, -8) and proinflammatory mediators (ICAM-1, iNOS and COX-2).   NF-kB is activated by a protein known as IKKs.   IkBa is a strong inhibitor of NF-kB but is rapidly degraded in response to a proinflammatory stimulus. This degradation allows the NF-kB to be free to translocate into the nucleus.  PARACTIN^® has anti-inflammatory effect by inhibiting the ICAM-1 expression in monocytes activated by TNF-a, suppresses the iNOS expression in cells stimulated by LPS/IFN-gamma, and inhibits microglial activation through the inhibition of iNOS and COX-2 expression. 

PARACTIN^® has shown diverse anti-inflammatory activities.   Here, we present evidence that PARACTIN^® inhibit NF-kB by directly interfering with the DNA binding of NF-kB.  PARACTIN^® prevents neither IkBa degradation nor MAPK phosphorylation following stimulating by PAF or fMLP.  The inhibition of the NF-kB activation by PARACTIN^® seems to be at an intracellular effect, and not at the level of the receptor, since PARACTIN^® inhibited the NF-kB activation induced by fMLP and PAF, factors that bind to different receptors coupling G proteins. Moreover, the intracellular calcium mobilization induced by PAF and fMLP was not affected by PARACTIN^® in the HL-60/Neutrophils cells.  PARACTIN^® did not reduce the calcium flux induced by fMLP in human neutrophils, and previously it has been demonstrated that PARACTIN^® did not inhibit the binding of PAF in membrane of bovine neutrophils. Therefore, PARACTIN^® seems to exert its anti-inflammatory response downstream the PAF or fMLP receptors. The p38 and ERK1/2 MAPK is intracellular pathway activated by PAF and fMLP, and play an important role in the NF-kB activation. It has been shown, that the inhibition of p38 reduces the NF-kB activation in neutrophils stimulated by LPS. In addition, blockage of the ERK1/2 pathway completely inhibits the activation of NF-kB induced by hydrogen peroxide. Therefore, we assessed the role of PARACTIN^® on MAPK inhibition. As expected, PAF or fMLP induced the MAPK phosphorylation in HL-60/Neutrophils cells. PARACTIN^® at doses that inhibited the NF-kB activation did not modified the MAPK. Additionally, it is evident that the inhibition of NF-kB activation by PARACTIN^® did not involve the degradation of IkBa or MAPK.  PARACTIN^® reduced significantly the DNA binding of NF-kB, induced by PAF and fMLP, both in vivo and in vitro.  Similarly, PARACTIN^® could also affect the expression of target genes controlled by NF-kB during inflammatory processes.

It is known that COX-2 expression is reduced by NF-kB inhibitors in endothelial cells stimulated by PAF (Marrache et al., 2002). In this study we demonstrated that PARACTIN^® reduced the COX-2 expression induced by PAF and fMLP in HL-60/neutrophils. In others cells, PARACTIN® reduced the COX-2 expression induced by LPS.  Previously, it has been demonstrated that PARACTIN^® suppresses the apoptosis in endothelial cells. NF-kB has been described to regulate the cellular process of apoptosis, through the anti-apoptotic proteins expression. This fact and the inhibition of NF-kB by PARACTIN^® shown by this research could explain the anti-proliferate effect of PARACTIN^®.  We conclude that PARACTIN^® is a new inhibitor of DNA binding of NF-kB exhibiting strong potential anti-inflammatory properties.

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