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Articles by F Kharas
Total Records ( 1 ) for F Kharas
  N. M Dagia , G Agarwal , D. V Kamath , A Chetrapal Kunwar , R. D Gupte , M. G Jadhav , S. S Dadarkar , J Trivedi , A. A Kulkarni Almeida , F Kharas , L. C Fonseca , S Kumar and M. R. Bhonde
 

A promising therapeutic approach to diminish pathological inflammation is to inhibit the increased production and/or biological activity of proinflammatory cytokines (e.g., TNF-, IL-6). The production of proinflammatory cytokines is controlled at the gene level by the activity of transcription factors, such as NF-B. Phosphatidylinositol 3-kinase (PI3K), a lipid kinase, is known to induce the activation of NF-B. Given this, we hypothesized that inhibitors of PI3K activation would demonstrate anti-inflammatory potential. Accordingly, we studied the effects of a preferential p110/ PI3K inhibitor (compound 8C; PIK-75) in inflammation-based assays. Mechanism-based assays utilizing human cells revealed that PIK-75-mediated inhibition of PI3K activation is associated with dramatic suppression of downstream signaling events, including AKT phosphorylation, IKK activation, and NF-B transcription. Cell-based assays revealed that PIK-75 potently and dose dependently inhibits in vitro and in vivo production of TNF- and IL-6, diminishes the induced expression of human endothelial cell adhesion molecules (E-selectin, ICAM-1, and VCAM-1), and blocks human monocyte-endothelial cell adhesion. Most importantly, PIK-75, when administered orally in a therapeutic regimen, significantly suppresses the macroscopic and histological abnormalities associated with dextran sulfate sodium-induced murine colitis. The efficacy of PIK-75 in attenuating experimental inflammation is mediated, at least in part, due to the downregulation of pertinent inflammatory mediators in the colon. Collectively, these results provide first evidence that PIK-75 possesses anti-inflammatory potential. Given that PIK-75 is known to exhibit anti-cancer activity, the findings from this study thus reinforce the cross-therapeutic functionality of potential drugs.

 
 
 
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