The mechanism of the antiulcer effect of omeprazole was studied placing emphasis on its role to block oxidative damage and apoptosis during ulceration. Dose-response studies on gastroprotection in stress and indomethacin-induced ulcer and inhibition of pylorus ligation-induced acid secretion indicate that omeprazole significantly blocks gastric lesions at lower dose (2.5 mg/kg) without inhibiting acid secretion, suggesting an independent mechanism for its antiulcer effect. Time course studies on gastroprotection and acid reduction also indicate that omeprazole almost completely blocks lesions at 1 h when acid inhibition is partial. The severity of lesions correlates well with the increased level of endogenous hydroxyl radical ( ⅐ OH), which when scavenged by dimethyl sulfoxide causes around 90% reduction of the lesions, indicating that ⅐ OH plays a major role in gastric damage. Omeprazole blocks stress-induced increased generation of ⅐ OH and associated lipid peroxidation and protein oxidation, indicating that its antioxidant role plays a major part in preventing oxidative damage. Omeprazole also prevents stress-induced DNA fragmentation, suggesting its antiapoptotic role to block cell death during ulceration. The oxidative damage of DNA by ⅐ OH generated in vitro is also protected by omeprazole or its analogue, lansoprazole. Lansoprazole when incubated in a ⅐ OH-generating system scavenges ⅐ OH to produce four oxidation products of which the major one in mass spectroscopy shows a molecular ion peak at m/z 385, which is 16 mass units higher than that of lansoprazole (m/z 369). The product shows no additional aromatic proton signal for aromatic hydroxylation in 1 H NMR. The product absorbing at 278 nm shows no alkaline shift for phenols, thereby excluding the formation of hydroxylansoprazole. The product is assigned to lansoprazole sulfone formed by the addition of one oxygen atom at the sulfur center following attack by the ⅐ OH. Thus, omeprazole plays a significant role in gastroprotection by acting as a potent antioxidant and antiapoptotic molecule.

Here we report that glioblastoma multiforme (GBM) mediates immunosuppression by promoting T-cell death via tumorassociated CD70 and gangliosides that act through receptordependent and receptor-independent pathways, respectively. GBM lines cocultured with T cells induced lymphocyte death. The GBM lines were characterized for their expression of CD70, Fas ligand (FasL), and tumor necrosis factor-A (TNF-A), and the possible participation of those molecules in T-cell killing was assessed by doing GBM/T cell cocultures in the presence of anti-CD70 antibodies, Fas fusion proteins, or anti-TNF-A antibodies. CD70 but not TNF-A or FasL is responsible for initiating T-cell death via the receptor-dependent pathway. Of the four GBM cell lines that induced T-cell death, three highly expressed CD70. Two nonapoptogenic GBM lines (CCF3 and U138), on the other hand, had only minimally detectable CD70 expression. Blocking experiments with the anti-CD70 antibody confirmed that elevated CD70 levels were involved in the apoptogenicity of the three GBM lines expressing that molecule. Gangliosides were found to participate in the induction of T-cell apoptosis, because the glucosylceramide synthase inhibitor (PPPP) significantly reduced the abilities of all four apoptogenic lines to kill the lymphocytes. Highperformance liquid chromatography (HPLC) and mass spectroscopy revealed that GM2, GM2-like gangliosides, and GD1a were synthesized in abundance by all four apoptogenic GBM lines but not by the two GBMs lacking activity. Furthermore, gangliosides isolated from GBM lines as well as HPLC fractions containing GM2 and GD1a were directly apoptogenic for T cells. Our results indicate that CD70 and gangliosides are both products synthesized by GBMs that may be key mediators of T-cell apoptosis and likely contribute to the T-cell dysfunction observed within the tumor microenvironment. (Cancer Res 2005; 65(12): 5428-38)

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The mechanism of the antiulcer effect of Neem leaf aqueous extract to block gastric lesions in rat has been studied with emphasis on acid secretion, oxidative damage and apoptosis. The extract dose-dependently inhibits gastric lesions induced by restraint-cold stress, indomethacin and ethanol. In stress ulcer model, it is more effective than ranitidine but less effective than omeprazole. It also dose-dependently blocks pylorus ligation and mercaptomethylimidazole-induced acid secretion. In the pylorus-ligation model, it is less effective than omeprazole but as effective as ranitidine. It inhibits H+-K+-ATPase activity in vitro in concentration-dependent manner to inhibit acid secretion. Oxidative membrane damage by hydroxyl radical (*OH) as measured by lipid peroxidation in stress ulcer is significantly blocked by leaf extract. Stress-induced apoptotic DNA fragmentation is also protected. The extract also prevents *OH-mediated mucosal DNA damage in vitro by scavenging the *OH. Neem leaf extract, thus, offers antiulcer activity by blocking acid secretion through inhibition of H+-K+-ATPase and by preventing oxidative damage and apoptosis.

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