Resveratrol has been reported to exert anticancer activity via modulation of multiple pathways and genes. In this study, we examined the effect of resveratrol on YD-10B human oral squamous cell carcinoma cells and its molecular mechanisms of action. We found that resveratrol inhibited the proliferation of YD-10B cells in a dose- and timedependent manner. The suppressive effect of resveratrol was accompanied by a reduction in Bmi-1 gene expression.We observed that silencing the Bmi-1 gene by small interfering RNA effectively downregulated the levels of GLUT1 mRNA and protein, which were also repressed by resveratrol. Bmi-1 silencing increased the number of YD-10B cells in S-phase arrest by approximately 2.3-fold compared with the control. In conclusion, the results of the present study demonstrate, for the first time, that resveratrol suppresses Bmi-1-mediated GLUT1 expression in human oral squamous cell carcinoma cells and suggest that the specific molecular targeting of Bmi-1 and/or GLUT1 expression can be combined with a chemotherapeutic strategy to improve the response of oral cancer cells to resveratrol.

Although anti-aging activities of melatonin, a hormone secreted by the pineal gland, have been reported in senescence-accelerated mouse models and several types of cells, its impact and mechanism on the senescence of human dental pulp cells (HDPCs) remains unknown. In this study, we examined the impact of melatonin on cellular premature senescence of HDPCs. Here, we found that melatonin markedly inhibited senescent characteristics of HDPCs after exposure to hydrogen peroxide (H₂O₂), including the increase in senescence-associated β-galactosidase (SA-β-gal)-positive HDPCs and the upregulation of p21 protein, an indicator for senescence. In addition, as melatonin attenuated H₂O₂-stimulated phosphorylation of c-Jun N-terminal kinase (JNK), while selective inhibition of JNK activity with SP600125 significantly attenuated H₂O₂-induced increase in SA-beta-gal activity. Results reveal that melatonin antagonizes premature senescence of HDPCs via JNK pathway. Thus, melatonin may have therapeutic potential to prevent stress-induced premature senescence, possibly correlated with development of dental pulp diseases, and to maintain oral health across the life span.
Aging* ; Animals ; Dental Pulp Diseases ; Dental Pulp* ; Humans* ; Hydrogen Peroxide ; JNK Mitogen-Activated Protein Kinases ; MAP Kinase Signaling System ; Melatonin* ; Mice ; Oral Health ; Phosphorylation ; Pineal Gland ; Up-Regulation

We demonstrate herein that silibinin, a polyphenolic flavonoid compound isolated from milk thistle (Silybum marianum), inhibits LPS-induced activation of macrophages and production of nitric oxide (NO) in RAW 264.7 cells. Western blot analysis showed silibinin inhibits iNOS gene expression. RT-PCR showed that silibinin inhibits iNOS, TNF-alpha, and IL1beta. We also showed that silibinin strongly inhibits p38 MAPK phosphorylation, whereas the ERK1/2 and JNK pathways are not inhibited. The p38 MAPK inhibitor abrogated the LPS-induced nitrite production, whereas the MEK-1 inhibitor did not affect the nitrite production. A molecular modeling study proposed a binding pose for silibinin targeting the ATP binding site of p38 MAPK (1OUK). Collectively, this series of experiments indicates that silibinin inhibits macrophage activation by blocking p38 MAPK signaling.
Adenosine Triphosphate ; Binding Sites ; Blotting, Western ; Gene Expression ; Macrophage Activation* ; Macrophages* ; MAP Kinase Signaling System ; Milk Thistle ; Models, Molecular ; Nitric Oxide ; p38 Mitogen-Activated Protein Kinases* ; Phosphorylation ; Tumor Necrosis Factor-alpha

Here, we show that radicicol, a fungal antibiotic, resulted in marked inhibition of inducible nitric oxide synthase (iNOS) transcription by the pancreatic beta cell line MIN6N8a in response to cytokine mixture (CM: TNF-alpha, IFN-gamma, and IL-1beta). Treatment of MIN6N8a cells with radicicol inhibited CM-stimulated activation of NF-kappaB/Rel, which plays a critical role in iNOS transcription, in a dose-related manner. Nitrite production in the presence of PD98059, a specific inhibitor of the extracellular signal-regulated protein kinase-1 and 2 (ERK1/2) pathway, was dramatically diminished, suggesting that the ERK1/2 pathway is involved in CM-induced iNOS expression. In contrast, SB203580, a specific inhibitor of p38, had no effect on nitrite generation. Collectively, this series of experiments indicates that radicicol inhibits iNOS gene expression by blocking ERK1/2 signaling. Due to the critical role that NO release plays in mediating destruction of pancreatic beta cells, the inhibitory effects of radicicol on iNOS expression suggest that radicicol may represent a useful anti-diabetic activity.
Flavonoids ; Gene Expression ; Imidazoles ; Insulin-Secreting Cells ; Macrolides ; Negotiating ; Nitric Oxide Synthase Type II ; Pyridines ; Tumor Necrosis Factor-alpha

BACKGROUND/AIMS: From the review of Korean literature most fatal mushroom poisonings have been due to amatoxins with high mortality. So far there have never been investigations on the amatoxins poisonings such as annual incidence, mortality, common causal species, and endemic areas. This study was carried out to develop some basic statistics as part of studies for an effective management of amatoxins intoxications. METHOD: For the year 1999 authors collected cases of mushroom poisonings which had been mainly gathered from hospitals nation-wide. All of the cases with suggestive amatoxins poisonings were screened by symptomatology and laboratory findings. The causal species of mushrooms were identified grossly and microscopically. RESULTS: A total of 54 victims with mushroom poisonings were evaluated. The causal mushroom toxins were diagnosed or strongly suggested as amatoxins in 43 of 54 victims. Eleven of 54 victims did not conform to the category of amatoxins intoxication due to absent or minimal elevation of aminotransferase. Mean age of the victims was 44.3 23.3 (range: 7-78) with male predominance (1.2 : 1). The causal species were confirmed, or strongly suggested, as Amanita virosa in 25 victims, Amanita subjunquillea in 14, and unknown species in 4. Thirty-five out of a total of 43 were regarded as moderate to severe intoxication (AST or ALT >1,000 IU/L) with 20% mortality. Most fatal victims showed marked thrombocytopenia (40,000 19,000/mm3) compared to non-fatal victims (109,066 42,245/mm3). A total of 88.4% of victims was developed in the Kangwon and Kyungpuk provinces. Both are west of the Taebaek Mountains (38/43). CONCLUSIONS: Although the common causal species for amatoxins poisonings in Korea are different from European countries and North America, the mortality is similar to that of those areas. In order to further reduce the mortality, bedside diagnostic methods using biological fluids and more effective therapy for liver failure should be established.
Agaricales ; Amanita ; Gangwon-do ; Humans ; Incidence ; Korea* ; Liver Failure ; Male ; Mortality ; Mushroom Poisoning ; North America ; Poisoning* ; Thrombocytopenia