No abstract

Ethyl pyruvate (EP), a simple aliphatic ester of pyruvic acid, has been shown to act as an anti-inflammatory molecule in various pathological conditions, which include sepsis or hemorrhagic shock. Recently, we showed that ethyl pyruvate has a neuroprotective effect in the postischemic brain and also in KA-induced pathogenesis in the brain. In this study, we examined whether aspirin augments neuroprotective effect of ethyl pyruvate in transient focal ischemia model by complementing the neuroprotective effects of ethyl pyruvate. Although, most of neuroprotective effect of aspirin has been attributed to the anti-platelet action, aspirin also has direct neuroprotective effects, including NF-kappaB inhibition. Ethyl pyruvate dose-dependently suppressed infarct formation in the postischemic brain, wherein intravenous administration of 5 mg/kg ethyl pyruvate 30 min after the occlusion reduced infarct volume to 34.5 +/- 15.5% (n = 6, P < 0.01) of that of the untreated control. In combination with aspirin (5 mg/kg, i.v.), the neuroprotective effect was enhanced, resulting in 16.0 +/- 5.9% (n = 6, P < 0.01) infarct volume. The time window for synergistic neuroprotection by ethyl pyruvate and aspirin extended to 9 h post-MCAO. The synergistic reduction in infarct volume was accompanied by suppression of the clinical manifestations associated with cerebral ischemia including motor impairment and neurological deficits. Inflammatory processes including microglial activation and proinflammatory cytokine expression were notably suppressed by the combination treatment in the postischemic brain and in primary microglia cultures, wherein ethyl pyruvate and aspirin modulate NF-kappaB signaling differentially. Aspirin interferes with IkappaB phosphorylation and degradation in the cytoplasm, possibly by specifically inhibiting IkappaB kinase-beta, whereas, the effect of ethyl pyruvate seems to occur in the nucleus, where it may interfere with the binding of NF-kappaB to responsive promoter elements in the target genes. Similar enhancement in neuroprotective effect was also observed in primary cortical cultures after NMDA or Zn(2+) treatment or oxygen-glucose deprivation. Together, these results indicate that combination treatment of ethyl pyruvate and aspirin affords synergistic neuroprotection in the postischemic brain with a wide therapeutic window, in part via differential modulation of the NF-kappaB signaling pathway.

Changes in bone metabolism among gastric cancer survivors have long been recognized. The aim of our study was to clarify the changes of bone mineral density (BMD) among gastric cancer survivors who underwent endoscopic resection or gastrectomy. Forty-nine patients diagnosed with tumor, node, and metastasis (TNM) stage 1 gastric cancer with pathologic confirmation, who underwent BMD measurement just before the procedure, and had no prior osteoporosis treatment, were studied. BMD was measured with dual energy x-ray absorptiometry before and after treatment. Laboratory tests were performed using fresh serum, and serum levels of alkaline phosphatase, albumin, calcium, and phosphorus were measured. We used a nested case-control design to compare groups. Of the 49 patients, 34 underwent gastrectomy and 15 underwent endoscopic treatment. There were no differences in baseline clinical characteristics, including BMD, and biochemical data between groups. The mean and median follow-up intervals for BMD measurement were 32.6 months (standard deviation, 16.5) and 31.0 months (interquartile range: 21.5, 41.0), respectively. The follow-up BMDs of the femoral neck and total hip were lower in the gastrectomy group (P = .010 and .011, respectively). The percentage changes in BMD for the lumbar spine, femoral neck, and total hip were −3.30%, −1.52%, and 0.40%, respectively, in the endoscopic treatment group, and −7.17%, −6.30%, and −3.49%, respectively, in the gastrectomy group. Bone loss of the lumbar spine and femoral neck were greater in the gastrectomy group (P = .028 and .022, respectively). BMD is lower after gastrectomy than after endoscopic treatment among early stage gastric cancer survivors.

We attempted to investigate molecular mechanisms underlying phenotypic change of vascular smooth muscle cells (VSMCs) by determining signaling molecules involved in chemokine production. Treatment of human aortic smooth muscle cells (HAoSMCs) with thrombin resulted not only in elevated transcription of the (C-C motif) ligand 11 (CCL11) gene but also in enhanced secretion of CCL11 protein. Co-treatment of HAoSMCs with GF109230X, an inhibitor of protein kinase C, or GW5074, an inhibitor of Raf-1 kinase, caused inhibition of ERK1/2 phosphorylation and significantly attenuated expression of CCL11 at transcriptional and protein levels induced by thrombin. Both Akt phosphorylation and CCL11 expression induced by thrombin were attenuated in the presence of pertussis toxin (PTX), an inhibitor of Gi protein-coupled receptor, or LY294002, a PI3K inhibitor. In addition, thrombin-induced production of CCL11 was significantly attenuated by pharmacological inhibition of Akt or MEK which phosphorylates ERK1/2. These results indicate that thrombin is likely to promote expression of CCL11 via PKC/Raf-1/ERK1/2 and PTX-sensitive protease-activated receptors/PI3K/Akt pathways in HAoSMCs. We propose that multiple signaling pathways are involved in change of VSMCs to a secretory phenotype.