Novel 4-azasteroidal N-glycoside analogues bearing sugar-like D ring: synthesis and anticancer activities.

A series of novel N-glycoside analogues with 4-azasteroid moiety bearing sugar-like D ring were conveniently synthesized by constructing the core dihydropyran ring embedded in 4-azasteroidal skeleton which was prepared from 4-aza-5α-androst-3,17-dione 1 in four steps. The structure of 6b were unambiguously proved by the appropriate X-ray structural analysis. Anticancer activity was found for all of the analogues with purinyl moiety against breast cancer (MCF-7), human neuroblastoma (SK-N-SH), cervical cancer cell (HeLa) and prostatic cancer (PC-3), while the analogue 7 containing 1,2,4-triazole heterocycle as the nucleobase was inactive against all of the tested cancer cell lines. The biology results showed the purinyl moiety attached to the pyran ring of 6a-d, substituent at 6'-position of purine base and introduction of a halogen atom at 2'-position of 6'-chloropurine had obviously effect on the evaluated anticancer activity.

[Changes in endothelial progenitor cells and their implications in multiple organ dysfunction syndrome caused by trauma in pigs].

OBJECTIVE: To investigate characteristics of changes in bone marrow endothelial progenitor cells (EPCs) and implications on multiple organ dysfunction syndrome (MODS) as a result of trauma. METHODS: Eighteen mini-pigs were randomized into two groups: MODS group (n=9) and control group (n=9). The animal models of MODS were reproduced by "two-hit" injury with hemorrhagic shock and lipopolysaccharide (LPS) injection. Bone marrow and peripheral blood of them were collected at five time points: normal condition (T1), before injection of LPS (T2), and 0 (T3), 24 (T4) and 48 hours (T5) after injection of LPS. Erythrocytic lysate was added to the samples, and the number of leucocytes in every sample was counted. The rate of EPCs in each sample was determined by flow cytometry. Number of EPCs in bone marrow and peripheral blood were calculated, and the results were analyzed statistically. RESULTS: The number of EPCs (x10(6)/L) in bone marrow of control group at T1-5 was 7.64+/-0.68, 7.32+/-0.55, 7.58+/-1.13, 7.77+/-0.70, and 7.88+/-0.84, respectively, and in peripheral blood control group was 3.54+/-0.26, 4.06+/-0.64, 3.74+/-0.55, 3.61+/-0.37, and 3.98+/-0.63, respectively. The number of EPCs (x10(6)/L) in bone marrow in the experimental group was 7.45+/-1.55, 6.58+/-0.80, 11.27+/-1.20, 10.88+/-1.15, and 8.36+/-2.88, respectively. The number of EPCs (x10(6)/L) in peripheral blood in the experimental group was 3.21+/-0.48, 8.71+/-2.04, 5.98+/-0.77, 1.27+/-0.91, and 2.14+/-0.96, respectively. The number of EPCs in bone marrow of experimental group was larger than that of control group at T3, T4, T5. The number of EPCs in the experimental group in peripheral blood was larger than that of control group at T2, T3, T4, T5. The number of EPCs in bone marrow was larger than that in peripheral blood at every time point (all P<0.05). CONCLUSION: The number of EPCs in peripheral blood elevates sharply in the earlier period, then plummeted quickly during MODS after a trauma. While the number of EPCs in bone marrow descends mildly at first, then rises obviously. Along with the aggravation of MODS, a declination of EPCs in bone marrow emerges. The change in bone marrow EPCs plays an important role in recovery of MODS.

[Influences of the phosphorylation of p38 mitogen activated protein kinase on gene expression of tumor necrosis factor-alpha in multiple organ dysfunction syndrome in pigs].

OBJECTIVE: To investigate that the phosphorylation of the p38 mitogen activated protein kinase (p38MAPK) influences gene expression of tumor necrosis factor-alpha (TNF-alpha) in multiple organ dysfunction syndrome (MODS) in pigs. METHODS: Thirty pigs were divided into MODS group and control group, and an animal model of MODS of "two-hit" injury, including hemorrhagic shock and endotoxemia, was reproduced. The content of p38MAPK's phosphorylation was assessed with Western blotting. TNF-alpha mRNA in peripheral blood monocytes was assayed with real time-polymerase chain reaction (RT-PCR). TNF-alpha was monitored in the peripheral blood plasma with enzyme linked immunosorbent assay (ELISA). RESULTS: Phosphorylation of p38MAPK was obviously increased in extent, which enhanced gene expression of TNF-alpha and then secretion of TNF-alpha by the peripheral blood mononuclear cell in MODS, and the differences were statistically significant compared with that of control group (P<0.05 or P<0.01). CONCLUSION: p38MAPK's phosphorylation is important in pathogenesis of MODS, and phosphorylation of p38MAPK can enhance TNF-alpha mRNA transcription and secretion of TNF-alpha from peripheral blood mononuclear cells, which is the mechanism of increased TNF-alpha in MODS.