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- Da, Jiping, et al.
(författare)
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Nitric oxied up-regulates the glucocorticoid receptor and blunts the inflammatory reaction in porcine endotoxin sepsis
- 2007
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Ingår i: Critical Care Medicine. - 0090-3493 .- 1530-0293. ; 35:1, s. 26-32
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: Nitric oxide inhibits the expression of many genes involved in inflammatory diseases. Glucocorticoids inhibit similar transcription factors. We hypothesized that there may be an interaction between nitric oxide and glucocorticoids, with the potential to enhance the anti-inflammatory effect when administered simultaneously. Design: Prospective, randomized, controlled study. Setting: Animal research laboratory. Subjects: A total of 45 anesthetized and mechanically ventilated pigs. Interventions: Lung and systemic injury was induced by intravenous infusion of endotoxin (lipopolysaccharide) for 6 hrs. After 2.5 hrs, one group received 3.5 mg/kg hydrocortisone, another group inhaled nitric oxide (30 ppm), and still another group received both steroid and nitric oxide. Control groups of healthy and endotoxin-exposed piglets were also studied. Measurements and Main Results: Central hemodynamics and gas exchange were measured. Detection of the glucocorticoid receptor and inflammatory markers in lung, liver, and kidney tissue were made by immunohistochemistry, and morphology was studied with light microscopy. Endotoxin infusion markedly reduced glucocorticoid receptor expression in lung, liver, and kidney and up-regulated activator protein-1 and the inflammatory markers nuclear factor-κB and tumor necrosis factor-a. When administered separately, steroids and nitric oxide had modest effect on the inflammatory response. However, nitric oxide up-regulated the glucocorticoid receptor expression. Simultaneous administration of steroids and nitric oxide attenuated the inflammatory response and almost preserved or restored normal histology of both lung and systemic organs. When the glucocorticoid receptor was blocked by a receptor antagonist (mifepristone, 600 mg) and inhaled nitric oxide was subsequently administered, no increase in the expression of the glucocorticoid receptor was seen. Conclusion: We suggest that up-regulation of glucocorticoid receptor expression by nitric oxide made steroid therapy more effective.
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| 2. |
- Li, Li, et al.
(författare)
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Antiproliferative activity and toxicity of 2-Methoxyestradiol in cervical cancer xenograft mice
- 2005
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Ingår i: International Journal of Gynecological Cancer. - 1048-891X .- 1525-1438. ; 15:2, s. 301-307
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Tidskriftsartikel (refereegranskat)abstract
- 2-methoxyestradiol (2-ME) is considered to be an effective anticancer compound for many types of tumors. We have previously demonstrated that 2-ME inhibits the growth of human cervical cancer HeLaS3 cells in vitro. In this study, we investigated the antitumoral effects of 2-ME on human cervical carcinoma in severe combined immune deficient (SCID) mice. The potential side effects of 2-ME on the SCID mice were also investigated. SCID mice were injected with HeLaS3 cells (3 x 10(6) to 4 x 10(6)/mouse) and a 15-day administration of 2-ME followed after a 1-week cell implantation. Tumor weight, volume, body weight, and blood chemistry were determined. Tumor tissues were examined with an antibody against the proliferative cell nuclear antigen and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) staining. Liver, spleen, kidney, heart, and lung were screened by pathologic examinations. 2-ME (75 mg/kg p.o.) inhibited growth of human cervical carcinoma by 34% (P < 0.05) as compared with control. Necrosis was found in both 2-ME-treated and untreated tumor tissues, but the necrotic area was larger in 2-ME-treated mice. A low expression of proliferative cell nuclear antigen and an increased number of apoptotic cells were found in 2-ME-treated tumor sections as compared to those in controls. No significant difference was detected in blood chemistry. In addition, the liver showed hyperplastic Kupffer cells, hydropic swelling of hepatocytes, and liquefactive necrosis. The spleen showed an increased number of megakaryocytes and apoptotic cells after 2-ME treatment. Thus, 2-ME has an antitumor effect on human cervical carcinoma, and it is toxic to liver and spleen in this mouse model.
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