Showing papers by "Alok C. Bharti published in 2002"

Piceatannol Inhibits TNF-Induced NF-κB Activation and NF-κB-Mediated Gene Expression Through Suppression of IκBα Kinase and p65 Phosphorylation

Abstract: Piceatannol is an anti-inflammatory, immunomodulatory, and anti-proliferative stilbene that has been shown to interfere with the cytokine signaling pathway. Previously, we have shown that resveratrol suppresses the activation of the nuclear transcription factor NF-κB. Piceatannol, previously reported as a selective inhibitor of protein tyrosine kinase Syk, is structurally homologous to resveratrol. Whether piceatannol can also suppress NF-κB activation was investigated. The treatment of human myeloid cells with piceatannol suppressed TNF-induced DNA binding activity of NF-κB. In contrast, stilbene or rhaponticin (another analog of piceatannol) had no effect, suggesting the critical role of hydroxyl groups. The effect of piceatannol was not restricted to myeloid cells, as TNF-induced NF-κB activation was also suppressed in lymphocyte and epithelial cells. Piceatannol also inhibited NF-κB activated by H 2 O 2 , PMA, LPS, okadaic acid, and ceramide. Piceatannol abrogated the expression of TNF-induced NF-κB-dependent reporter gene and of matrix metalloprotease-9, cyclooxygenase-2, and cyclin D1. When examined for the mechanism, we found that piceatannol inhibited TNF-induced IκBα phosphorylation, p65 phosphorylation, p65 nuclear translocation, and IκBα kinase activation, but had no significant effect on IκBα degradation. Piceatannol inhibited NF-κB in cells with deleted Syk, indicating the lack of involvement of this kinase. Overall, our results clearly demonstrate that hydroxyl groups of stilbenes are critical and that piceatannol, a tetrahydroxystilbene, suppresses NF-κB activation induced by various inflammatory agents through inhibition of IκBα kinase and p65 phosphorylation.

The role of TNF and its family members in inflammation and cancer: lessons from gene deletion.

Abstract: Almost two decades ago, tumor necrosis factor (TNF) was identified as a protein produced by the immune system that played a major role in suppression of tumor cell proliferation. Extensive research since then has revealed that TNF is a major mediator of inflammation, viral replication, tumor metastasis, transplant rejection, rheumatoid arthritis, and septic shock. As of today, 18 different members of the TNF superfamily have been identified, and most of them have been found to mediate a wide variety of diseases including cancer, arthritis, bone resorption, allergy, diabetes, atherosclerosis, myocardial infarction, graft versus host disease, and acquired immune deficiency disease. All the cytokines of the TNF superfamily mediate their effects through the activation of the transcription factor NF-kappaB, c-Jun N-terminal kinase, apoptosis, and proliferation. Thus, agents that can either suppress the production of these cytokines or block their action have therapeutic value for a wide variety of diseases. In this review, we have elucidated the signal transduction pathways used by the members of the TNF family and the effects of deletion of genes that mediate the pathways. Our current understanding of the signaling pathways for TNF and other family members could serve as a target for the development of therapeutics.

Chemopreventive agents induce suppression of nuclear factor-κB leading to chemosensitization

Abstract: Nuclear factor-kappaB (NF-kappaB), a transcription factor, is present normally in the cytoplasm as an inactive heterotrimer consisting of p50, p65, and IkappaBalpha subunits. When activated, NF-kappaB translocates to the nucleus as a p50-p65 heterodimer. This factor regulates the expression of various genes that control apoptosis, viral replication, tumorigenesis, various autoimmune diseases, and inflammation. NF-kappaB has been linked to the development of carcinogenesis for several reasons. First, various carcinogens and tumor promoters have been shown to activate NF-kappaB. Second, activation of NF-kappaB has been shown to block apoptosis and promote proliferation. Third, the tumor microenvironment can induce NF-kappaB activation. Fourth, constitutive expression of NF-kappaB is frequently found in tumor cells. Fifth, NF-kappaB activation induces resistance to chemotherapeutic agents. Sixth, several genes involved in tumor initiation, promotion, and metastasis are regulated by NF-kappaB. Seventh, various chemopreventive agents have been found to down-regulate the NF-kappaB activation. All these observation suggest that NF-kappaB could mediate tumorigenesis and thus can be used as a target for chemoprevention and for the treatment of cancer. Agents that suppress NF-kappaB activation can suppress the expression of genes involved in carcinogenesis and tumorigenesis in vivo.