• Journal of Nutrition and Health
• /
• v.42 no.5
• /
• pp.423-433
• /
• 2009

Folate and vitamin $B_{12}$ are essential cofactors for homocysteine (Hcy) metabolism. Homocysteinemia has been related with cardiovascular and neurodegenerative disease. We examined the effect of folate and/or vitamin $B_{12}$ deficiency on biomarkers of one carbon metabolism in blood, liver and brain, and analyzed the correlation between vitamin biomarkers in mild and moderate homocysteinemia. In this study, Sprague-Dawley male rats (5 groups, n = 10) were fed folatesufficient diet (FS), folate-deficient diet (FD) with 0 or 3 g homocystine (FSH and FDH), and folate-/vitamin $B_{12}$-deficient diet with 3 g homocystine (FDHCD) for 8 weeks. The FDH diet induced mild homocysteinemia (plasma Hcy 17.41 ${\pm}$ 1.94 nmol/mL) and the FDHCD diet induced moderate homocysteinemia (plasma Hcy 44.13 ${\pm}$ 2.65 nmol/mL), respectively. Although liver and brain folate levels were significantly lower compared with those values of rats fed FS or FSH (p < 0.001, p < 0.01 respectively), there were no significant differences in folate levels in liver and brain among the rats fed FD, FDH and FDHCD diet. However, rats fed FDHCD showed higher plasma folate levels (126.5 ${\pm}$ 9.6 nmol/L) compared with rats fed FD and FDH (21.1 ${\pm}$ 1.4 nmol/L, 22.0 ${\pm}$ 2.2 nmol/L)(p < 0.001), which is the feature of "ethyl-folate trap"by vitamin $B_{12}$ deficiency. Plasma Hcy was correlated with hepatic folate (r = -0.641, p < 0.01) but not with plasma folate or brain folate in this experimental condition. However, as we eliminated FDHCD group during correlation test, plasma Hcy was correlated with plasma folate (r = -0.581, p < 0.01), hepatic folate (r = -0.684, p < 0.01) and brain folate (r = -0.321, p < 0.05). Hepatic S-adenosylmethionine (SAM) level was lower in rats fed FD, FDH and FDHCD than in rats fed FS and FSH (p < 0.001, p < 0.001 respectively) and hepatic S-adenosylhomocysteine (SAH) level was significantly higher in those groups. The SAH level in brain was also significantly increased in rats fed FDHCD (p < 0.05). However, brain SAM level was not affected by folate and/or vitamin $B_{12}$ deficiency. This result suggests that dietary folate- and vitamin B12-deficiency may inhibit methylation in brain by increasing SAH rather than decreasing SAM level, which may be closely associated with impaired cognitive function in nutritional homocysteinemia.

• Tuberculosis and Respiratory Diseases
• /
• v.49 no.6
• /
• pp.691-702
• /
• 2000

Background : Acute lung injury (ALI) is a commonly encountered respiratory disease and its prognosis is poor when the treatment is not provided promptly and properly. However no specific pharmacologic treatment is currently available for ALI, although recently several supportive drugs have been under scrutiny. We studied anti-inflammatory effects of pentoxifylline (PF), a methylated xanthine, and ONO-5046, a synthetic neutrophil elastase inhibitor on lipopolysaccharide (LPS)-induced ALI in vitro. Methods : To establish an in vitro model of LPS-induced ALI, primary rat alveolar macrophages and peripheral neutrophils in various ratios (1:0, 5:1, 1:1, 1:5, 0:1) were co-cultured with transformed rat alveolar epithelial cells (L2 cell line) or vascular endothelial cells (IP2-E4 cell line) under LPS stimulation. Each experiment was divided into five groups-control, LPS, LPS+PF, LPS+ONO, and LPS+PF+ONO. We compared LPS-induced superoxide anion productions from primary rat alveolar macrophages and peripheral neutrophils in various ratios, and the resultant cytotoxicity on L2 cells or IP2-E4 cells between groups. In addition we also compared the productions of tumor necrosis factor (TNF)-$\alpha$ interleukin (IL)-$1{\beta}$, monocyte chemotactic protein(MCP)-1, IL-6, and IL-10 as well as mRNA expressions of TNF-$\alpha$ inducible nitric oxide synthetase(iNOS), and MCP-1 from LPS-stimulated primary rat alveolar macrophages between groups. Results : (1) PF and ONO-5046 in each or both showed a trend to suppress LPS-induced superoxide anion productions from primary rat alveolar macrophages and peripheral neutrophils regardless of their ratio, except for the LPS+PF+ONO group with the 1:5 ratio, although statistical significance was limited to a few selected experimental conditions. (2) PF and ONO-5046 in each or both showed a trend to prevent IP2-E4 cells from LPS-induced cytotoxicity by primary rat alveolar macrophages and peripheral neutrophils regardless their ratio, although statistical significance was limited to a few selected experimental conditions. the effects of PF and/or ONO-5046 on LPS-induced L2 cell cytotoxicity varied according to experimental conditions. (3) PF showed a trend to inhibit LPS-induced productions of INF-$\alpha$ MCP-1, and IL-10 from primary rat alveolar macrophages. ONO-5046 alone didnot affect the LPS-induced productions of proinflammatory cytokines from primary rat alveolar macrophages but the combination of PF and ONO-5046 showed a trend to suppress LPS-induced productions of INF-$\alpha$ and IL-10 PF and ONO-5046 in each or both showed a trend to increase LPS-induced IL-$\beta$ and IL-6 productions from primary rat alveolar macrophages. (4) PF and ONO-5046 in each or both showed a trend to attenuate LPS-induced mRNA expressions of TNF-$\alpha$ and MCP-1 from primary rat alveolar macrophages but at the same time showed a trend increase iNOS mRNA expression. Conclusion : These results suggest that PF and ONO-5046 may play a role in attenuating inflammation in LPS-induced ALI and that further study is needed to use these drugs as a new supportive therapeutic strategy for ALI.

• Radiation Oncology Journal
• /
• v.16 no.3
• /
• pp.291-301
• /
• 1998

Purpose : A retrospective study was conducted comparing single daily fraction (SDF) thoracic radiotherapy (TRT) with twice daily (BID) TRT to determine the potential benefit of BID TRT in limited-stage small cell lung cancer (SCLC). Endpoints of the study were response. survival, pattern of failure, and acute toxicity. Materials and Methods : Between November 1989 to December 1996, 78 patients with histologically proven limited-stage SCLC were treated at the Department of Therapeutic Radiology, Chungnam National University Hospital. Of these, 9 were irradiated for palliative intent, and 1 had recurrent disease. Remaining 68 patients were enrolled in this study. There were 26 patients with a median age of 58 years, and 22 (85$\%$) ECOG performance score of less than 1 in SDF TRT. There were 42 patients with a median age of 57 years, and 36 (86$\%$) ECOG performance score of less than 1 in BID TRT By radiation fractionation regimen, there were 26 in SDF TRT and 42 in BID TRT. SDF TRT consisted of 180 cGy, 5 days a week. BID TRT consisted of 150 cGy BID, 5 days a week in 13 of 42 and 120 cGy BID, in 29 of 42. And the twice daily fractions were separated by at least 4 hours. Total radiotherapy doses were between 5040 and 6940 cGy (median, 5040 cGy) in SDF TRT and was between 4320 and 5100 cGy (median, 4560 cGy) in BID TRT. Prophylactic cranial irradiation (PCI) was recommended for patients who achieved a CR. The recommended PCI dose was 2500 cGy/10 fractions. Chemotherapy consisted of CAV (cytoxan 1000 mg/$m^2$, adriamycin 40 mg/$m^2$, vincristine 1 mg/$m^2$) alternating with VPP (cisplatin 60 mg/$m^2$, etoposide 100 mg/$m^2$) every 3 weeks in 25 (96$\%$) of SDF TRT and in 40 (95$\%$) of BID TRT. Median cycle of chemotherapy was six in both group. Timing for chemotherapy was sequential in 23 of SDF TRT and in 3 BID TRT, and concurrent in 3 of SDF TRT and in 39 of BID TRT Follow-up ranged from 2 to 99 months (median, 14 months) in both groups. Results : Of the 26 SDF TRT, 9 (35$\%$) achieved a complete response (CR) and 14 (54$\%$) experienced a partial response (PR). Of the 42 BID TRT, 18 (43$\%$) achieved a CR and 23 (55$\%$) experienced a PR. There was no significant response difference between the two arms (p=0.119). Overall median and 2-year survival were 15 months and 26.8$\%$, respectively. The 2-year survivals were 26.9$\%$ and 28$\%$ in both arm, respectively (p=0.51). The 2-rear survivals were 35$\%$ in CR and 24.2$\%$ in PR, respectively. The grade 2 to 3 esophageal toxicities and grade 2 to 4 neutropenias were more common in BID TRT (p=0.028 0.003). There was no difference in locoregional and distant metastasis between the two arms (p=0 125 and 0.335, respectively). The most common site of distant metastasis was the brain. Conclusion : The median survival and 2-year survival were 17 months and 20.9$\%$ in SDF TRT with sequential chemotherapy, and 15 months and 28$\%$ in BID TRT with concurrent chemotherapy, respectively. We did not observe a substantial improvement of long-term survival in the BID TRT with concurrent chemotherapy compared with standard schedules of SDF TRT with sequential chemotherapy. The grade 2 to 3 esophageal toxicities and glade 2 to 4 neutropenias were more common in BID TRT with concurrent chemotherapy. Although the acute toxicities were more common in BID TRT with concurrent chemotherapy than SDF TRT with sequential chemotherapy, a concurrent chemotherapy and twice daily TRT was feasible. However further patient accrual and long-term follow up are needed to determine the potential benefits of BID TRT in limited-stage SCLC.