Traditional Chinese medicine (TCM) has been practiced for thousands of years and at the present time is widely accepted as an alternative treatment for cancer. In this review, we sought to summarize the molecular and cellular mechanisms underlying the chemopreventive and therapeutic activity of TCM, especially that of the Chinese herbal medicine‐derived phytochemicals curcumin, resveratrol, and berberine. Numerous genes have been reported to be involved when using TCM treatments and so we have selectively highlighted the role of a number of oncogene and tumor suppressor genes in TCM therapy. In addition, the impact of TCM treatment on DNA methylation, histone modification, and the regulation of noncoding RNAs is discussed. Furthermore, we have highlighted studies of TCM therapy that modulate the tumor microenvironment and eliminate cancer stem cells. The information compiled in this review will serve as a solid foundation to formulate hypotheses for future studies on TCM‐based cancer therapy.

To date no authentic embryonic stem cell (ESC) line or germline-competent-induced pluripotent stem cell (iPSC) line has been established for large animals. Despite this fact, there is an impression in the field that large animal ESCs or iPSCs are as good as mouse counterparts. Clarification of this issue is important for a healthy advancement of the stem cell field. Elucidation of the causes of this failure in obtaining high quality iPSCs/ESCs may offer essential clues for eventual establishment of authentic ESCs for large animals including humans. To this end, we first generated porcine iPSCs using nonintegrating replicating episomal plasmids. Although these porcine iPSCs met most pluripotency criteria, they could neither generate cloned piglets through nuclear transfer, nor contribute to later stage chimeras through morula injections or aggregations. We found that the reprogramming genes in iPSCs could not be removed even under negative selection, indicating they are required to maintain self-renewal. The persistent expression of these genes in porcine iPSCs in turn caused differentiation defects in vivo. Therefore, incomplete reprogramming manifested by a reliance on sustained expression of exogenous-reprogramming factors appears to be the main reason for the inability of porcine iPSCs to form iPSC-derived piglets.

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Glutamate transporters regulate extracellular concentrations of glutamate, an excitatory neurotransmitter in the central nervous system. We have shown that the commonly used anesthetic isoflurane increased the activity of glutamate transporter type 3 (excitatory amino acid transporter 3, EAAT3) possibly via a protein kinase C (PKC)-dependent pathway. In this study, we showed that isoflurane induced a time-and concentrationdependent redistribution of EAAT3 to the cell membrane in C6 glioma cells. This redistribution was inhibited by staurosporine, a pan PKC inhibitor, or by 12-(2-cyanoethyl)-6,7,12,13-tetrahydro-13-methyl-5-oxo-5H-indolo(2,3-a)pyrrolo(3,4-c)-carbazole (Gö 6976) at a concentration that selectively inhibits conventional PKC isozymes (PKC␣, -␤, and -␥). This isoflurane-induced EAAT3 redistribution was also blocked when the expression of PKC␣ but not PKC␤ proteins was down-regulated by the respective antisense oligonucleotides. The isoflurane-induced increase of glutamate uptake by EAAT3 was abolished by the down-regulation of PKC␣ expression. Immunoprecipitation with an anti-EAAT3 antibody pulled down more PKC␣ in cells exposed to isoflurane than in control cells. Isoflurane also increased the phosphorylated EAAT3 and the redistribution of PKC␣ to the particulate fraction of cells. Consistent with the results in C6 cells, isoflurane also increased EAAT3 cell-surface expression and enhanced the association of PKC␣ with EAAT3 in rat hippocampal synaptosomes. Our results suggest that the isoflurane-induced increase in EAAT3 activity requires an increased amount of EAAT3 protein in the plasma membrane. These effects are PKC␣-dependent and may rely on the formation of an EAAT3-PKC␣ complex. Together, these results suggest an important mechanism for the regulation of glutamate transporter functions and expand our understanding of isoflurane pharmacology at cellular and molecular levels.Glutamate transporters (also called excitatory amino acid transporters, EAAT) are important in regulating extracellular concentrations of glutamate (Danbolt, 2001), a major excitatory neurotransmitter in the mammalian central nervous system (CNS). By transporting glutamate from extracellular to intracellular space under physiological conditions, EAATs prevent extracellular glutamate accumulation and regulate glutamate neurotransmission. Five EAATs have been identified: EAAT1 to EAAT5 (Danbolt, 2001). In rats, EAAT1 and EAAT2 are found in glial cells, and EAAT3 and EAAT4 are mainly expressed in neurons, whereas EAAT5 is located in neurons and glial cells of retina (Rothstein et al., 1994;Lehre et al., 1995;Arriza et al., 1997). The transporting functions of all five EAATs are sodium-dependent. They use the transmembrane gradient of Na ϩ , K ϩ , and H ϩ as a driving force to uptake glutamate (Billups et al., 1998;Danbolt, 2001).Studies on regional distribution of EAATs have shown that EAAT3 is widely distributed in forebrain, hippocampus, and cerebellum and that EAAT4 is largely restricted to the molecular cell layer ...

We have shown that exposure of neurons to opioid immediately before ischemia induces ischemia tolerance. This phenomenon is called acute opioid preconditioning. In this study, we test the hypothesis that opioids induce delayed neuropreconditioning (from hours to days after opioid exposure). Exposure to morphine, an agonist for delta-, mu-, and kappa-opioid receptors, or Tan-67, a selective delta1-receptor agonist, for 30 minutes at 24 hours before a 35-minute oxygen-glucose deprivation (OGD, to simulate ischemia in vitro) dose-dependently reduced the OGD-induced neuronal death in the CA1 region of the rat organotypic hippocampal slice cultures. The morphine preconditioning-induced neuroprotection was inhibited by beta-funaltrexamine, a mu-opioid receptor antagonist, but not by 7-benzylidenenaltrexone, a delta1-receptor antagonist, or nor-binaltorphimine, a kappa-receptor antagonist. The Tan-67 preconditioning-induced neuroprotection was inhibited by 7-benzylidenenaltrexone. The combination of morphine and Tan-67 did not induce a better preconditioning effect than did morphine or Tan-67 alone. Application of morphine and Tan-67 at 24 hours before permanent right middle cerebral arterial occlusion reduced brain infarct volume and improved neurologic functional outcome assessed 24 hours after the occlusion in adult male rats. These results suggest that morphine and Tan-67 induce a delayed preconditioning effect in the brain under in vivo and in vitro conditions. Whereas the delayed phase of morphine preconditioning may involve mu-opioid receptors, Tan-67 preconditioning may be mediated by delta1-opioid receptors. Morphine and Tan-67 may activate a shared intracellular signaling pathway to induce the delayed preconditioning effects in the brain.