SUMMARY:Tumor-induced angiogenesis is a prerequisite for excessive tumor growth. Blood vessels invade the tumor tissue after degradation of the extracellular matrix scaffold by matrix metalloproteinases (MMPs). Inhibition of MMPs has been therefore suggested to be a useful tool to abolish neoangiogenesis of solid tumors. In the present study, antioxidative plant ingredients used in traditional Chinese medicine were investigated for their capacity to down-regulate MMP expression and to inhibit angiogenesis in embryonic stem cell-derived embryoid bodies and tumor-induced angiogenesis in confrontation cultures consisting of embryoid bodies and multicellular DU-145 prostate tumor spheroids. Embryoid bodies transiently expressed MMP-1, MMP-2, and MMP-9 during the time of differentiation of capillary-like structures. In confrontation cultures, MMP expression was increased compared with control tumor spheroids and embryoid bodies cultivated separately. The increased expression of MMPs in confrontation cultures was a result of elevated levels of reactive oxygen species (ROS) upon confrontation culture and was totally abolished in the presence of the free radical scavenger vitamin E. Incubation of embryoid bodies with baicalein, epicatechin, berberine, and acteoside, which are herbal ingredients used in traditional Chinese medicine, significantly inhibited angiogenesis in embryoid bodies and decreased intracellular ROS levels. Tumor-induced angiogenesis in confrontation cultures was totally abolished in the presence of the free radical scavenger vitamin E. Because herbal ingredients down-regulated MMP expression, we conclude that ROS generated during confrontation culture induce the expression of MMPs that are necessary for endothelial cell invasion into the tumor tissue. (Lab Invest 2003, 83:87-98).

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Although the bioaccumulation of organophosphate flame retardants (OPFRs) in aquatic organisms has been investigated, little information is available about their bioaccumulation in mammals following chronic inhalation exposure. To address this knowledge gap, C57BL/6 mice were exposed to 7 PM 2.5 -associated OPFRs via the trachea to study their bioaccumulation, tissue distribution, and urinary metabolites. Low (corresponding to the real PM 2.5 concentrations occurring during winter in Guangzhou), medium, and high dosages were examined. After 72 days' exposure, ∑OPFR concentrations in tissues from mice in the medium dosage group decreased in the order of intestine > heart > stomach > testis > kidney > spleen > brain > liver > lung > muscle. Of the OPFRs detected in all three exposure groups, chlorinated alkyl OPFRs were most heavily accumulated in mice. We found a significant positive correlation between the bioaccumulation ratio and octanol−air partition coefficient (K OA ) in mice tissues for low log K OW OPFR congeners (log K OW ≤ 4, p < 0.05). Three urinary metabolites (di-p-cresyl phosphate: DCrP, diphenyl phosphate: DPhP, dibutyl phosphate: DnBP) were detected from the high dosage group. These results provide important insights into the bioaccumulation potential of OPFRs in mammals and emphasize the health risk of chlorinated alkyl OPFRs.

Embryonic stem cells (ESCs) can uniquely proliferate indefinitely and differentiate into all cell lineages. ESCs may therefore provide an unlimited supply of cells for cell-based therapies. Previous study reported the presence of hyperpolarization-activated inward currents in undifferentiated mouse (m) ESCs, but the functional role of this hyperpolarization-activated current in mESCs is unknown. In this study, the role of this current in maintaining the proliferative capacity and the cell cycle progression of ESCs was investigated. In D3 mESCs, this hyperpolarization-activated inward current can be blocked by HCN channel blocker ZD7288. Application of the HCN channel blockers, cesium (1-10 mM) or ZD7288 (0.1-30 μM), attenuated cell proliferation in a concentration-dependent manner. Both HCN blockers were found to be non-cytotoxic to mESCs as determined by cell viability test. Interestingly, ZD7288 at 10 and 30 μM was found to decrease the proportion of cells in G(0)/G(1) phase and increase the proportion of cells in S phase. This suggests that this hyperpolarization-activated current can affect the cell cycle progression in mESCs. In summary, the present investigation suggests that ESC proliferation and cell cycle progression can be regulated by this hyperpolarization-activated current.