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 H2O2, 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.

Methotrexate (MTX), a folate antagonist, is a commonly used anti-inflammatory, antiproliferative, and immunosuppressive drug whose mode of action is not fully established. Due to the central role of NF-κB in these responses, we postulated that MTX must mediate its effects through suppression of NF-κB activation. We investigated the effects of MTX on NF-κB activation induced by TNF in Jurkat cells. The treatment of these cells with MTX suppressed TNF-induced NF-κB activation with optimum effects occurring at 10 μM MTX for 60 min. These effects were not restricted to Jurkat cells because other cell types were also inhibited. Besides TNF, MTX also suppressed the NF-κB activation induced by various other inflammatory stimuli. The suppression of TNF-induced NF-κB activation by MTX correlated with inhibition of IκBα degradation, suppression of IκBα phosphorylation, abrogation of IκBα kinase activation, and inhibition of NF-κB-dependent reporter gene expression. Because ecto 5′ nucleotidase inhibitor (α,β-methylene adenosine-5′-diphosphate) blocked the effect of MTX, adenosine mimicked the effect of MTX, and adenosine A2b receptor antagonist (3,7-dimethyl-1-propargylxanthine) reversed the inhibitory effect of MTX, we suggest that MTX suppresses NF-κB activation by releasing adenosine. A partial reversal of MTX-induced NF-κB suppression by thymidine and folinic acid indicates the role of the thymidylate synthase pathway also. Overall, our results clearly demonstrate that MTX suppresses NF-κB activation through the release of adenosine, which may contribute to the role of MTX in anti-inflammatory, immunomodulatory, and antiproliferative effects.

Renal injury due to perinatal asphyxia has not been systematically evaluated. The available studies have used variable definitions, incomplete investigations and none had a control group. The aim of this study was to evaluate systematically the renal functions in severely asphyxiated newborns and to find if abnormal renal function tests can predict adverse outcome (death or neurologic abnormality at discharge). In a prospective case-control design, 25 inborn babies>or=34 weeks gestation having asphyxia (5 min Apgaror=5 min) were enrolled as 'cases'. Simultaneously 25 gestation and weight matched babies with no asphyxia were enrolled as 'controls'. Renal function tests, calculated renal indices using timed urine collections and excretion of beta2-microglobulin and N-acetyl-beta-D-glucosaminidase (NAG) were monitored in both the groups for first 4 days of life. Fourteen (56 per cent) asphyxiated babies had acute renal failure (ARF) as compared to 1 (4 per cent) control (p=0.002). Blood urea and serum creatinine values were significantly higher in asphyxiated babies on day 4 but not on day 2. Renal failure index and FeNa were higher in asphyxiated babies on both day 2 and day 4, but creatinine clearance was not different. Urinary excretion of both beta2-microglobulin and NAG was higher in the asphyxiated babies on day 2 as well as day 4. Five minute Apgar1.5 mg/dl alone had the best specificity and positive predictive value. The renal parameters were however poorer predictors of adverse outcome in comparison to clinical markers like 5 min Apgar

With the use of monoclonal antibodies (mAb) and immunohistology, the numbers of phenotypically distinct cells infiltrating lung tissue from 15 postmortem (PM) cases of fatal asthma were quantified and compared with 6 cases of cystic fibrosis (CF) (three postmortem, three transplant) and 10 nonasthmatic cases of sudden death matched for age and sex. Tissue eosinophilia was significantly greater (p less than 0.001) in the fatal asthma group than in the CF or sudden death controls. In asthma, approximately 40% of the eosinophilic infiltrate was EG2 positive (an indication of eosinophil activation and secretion of eosinophil cationic protein). The numbers of eosinophils and EG2 positive cells were significantly elevated in the subjects with acute severe asthma who had had a duration of terminal illness exceeding, as compared with less than, 24 h (p less than 0.05). When compared with the sudden death controls, there were increases in the numbers of Dako L C positive cells (i.e., CD45 positive "total leukocytes") in both fatal asthma and CF (p less than 0.01 and 0.05, respectively). The mean number of MT-1 positive (T) cells in the asthma and CF groups was approximately twice that of the control (p less than 0.05 and 0.01, respectively). The mean number of MB2 positive (B) cells was similar for both the asthma and sudden death control groups but was significantly increased in CF (p less than 0.05). The average T:B cell ratios were 6:1, 1:1, and 2:1 in the fatal asthma, CF, and control groups, respectively. The results support a role for the T lymphocyte in the pathogenesis of fatal asthma and CF.(ABSTRACT TRUNCATED AT 250 WORDS)

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