Discovery of anti-hepatoma agents from 1,4,5,6,7,8-hexahydropyrido[4,3-d]pyrimidine by inhibiting PI3K/AKT/NF-κB pathway activation.

In order to obtain new anti-hepatoma drugs with low toxicity, some 1,4,5,6,7,8-hexahydropyrido[4,3-d]pyrimidines (PPMs, 4a-t) were synthesized in this study. Many of them showed significant anti-hepatoma effects against HCC cells and low toxicity toward HHL-5 cells. Combined with their anti-hepatoma activity and toxicity, 4-CF3-substituted 4k was selected as an effective lead compound. Preliminary mechanistic studies revealed that 4k could up-regulate the expression levels of Bax and caspase-3 proteins, down-regulate the expression levels of Bcl-2 protein, promote significant apoptosis of HepG2, and block cells in G2-M phase to prevent cells from completing mitosis. Also, 4k could significantly inhibit the activation of PI3K/AKT/NF-κB pathway by blocking the phosphorylation of PI3K, AKT, NF-κB/p65 and IFN-γ-induced nuclear transport. Docking analysis showed that 4k could reasonably bind to the active sites of Bcl-2, NF-κB/p65, PI3K and AKT. This result suggested that 4k could be used as a new type of NF-κB inhibitor, which provides a scientific basis for further research into the treatment of hepatoma.

[Ion distribution, absorption and translocation characteristics of Alhagi sparsifolia in adaptation to saline habitat.] / 疏叶骆驼刺适应盐渍生境的离子分布、吸收和运输特征.

In order to explore the adaptive capacity of Alhagi sparsifolia to soil salinity (mild, mo-derate, severe saline soil), the distribution, adsorption and translocation characteristics of Na+, K+, Ca2+, Mg2+ in different organs of A. sparsifolia, which is a dominant native vegetation in southern edge of Tarim basin, were investigated. The results showed that when grown on a mild and moderate saline soil, Na+ distribution in different organs of A. sparsifolia followed the order of stem≈thorn>leaf>root; when grown on a severe saline soil, Na+ distribution followed leaf>stem≈thorn>root. The distribution of Ca2+ and Mg2+ followed leaf >thorn>stem>root. With the increase of soil salt level, Na+ content in different organs of A. sparsifolia increased, while K+ content in leave decreased; meanwhile the increasing soil salt level significantly decreased the K+/Na+ ratio in both root and leave, as well as the Ca2+/Na+ and Mg2+/Na+ ratios in all organs. The selective transportation coefficients for Ca2+-Na+ and Mg2+-Na+ followed order of stem-leaf>stem-thorn>root-stem under saline habitats. Based on the integrated analysis, in order to adapt to salinity habitat, A. sparsifolia could use multiple organs to accumulate Na+, depending on soil salt level. Na+ could accumulate in stem and thorn at a relative low level, but in leaves at high levels. Besides, Ca2+ and Mg2+ could be the inorganic osmotic adjustment substances for A. sparsifolia to adapt the saline environment.