Adipose tissue-derived mesenchymal stem cells (AD-MSCs), which can differentiate into several lineages, have immunomodulatory properties similar to those of bone marrow-derived MSCs. However, the specific mechanism by which the immunomodulatory effect of MSCs occurs is not clear. In this study, we isolated canine AD-MSCs (cAD-MSCs) and induced their development into adipocyte, osteocyte, and neuron-like cells. We then investigated their phenotype and cytokine expression to determine whether they were able to exert an immunomodulatory effect and what the underlying mechanisms of this effect were. cAD-MSCs expressed CD44, CD90, and MHC class I and were also partially positive for the expression of CD34; however, they did not express CD14 and CD45. In addition, they expressed the mRNA of transforming growth factor beta (TGF-beta), IL-6, IL-8, CCL2, CCL5, vascular endothelial growth factor, hepatocyte growth factor (HGF), tissue inhibitor metalloproteinase-1/2, and cyclooxygenase-2 but not that of IL-10. Further, leukocyte proliferation induced by mitogens was suppressed when they were cocultured with irradiated cAD-MSCs, as well as with culture supernatants of cAD-MSCs alone. Moreover, TNF-alpha production significantly decreased, whereas TGF-beta, IL-6, and interferon-gamma production significantly increased in cAD-MSCs that were cocultured with leukocytes. Finally, immonomodulatory factors of MSCs, such as TGF-beta, HGF, prostaglandin E2 (PGE2), and indoleamine 2, 3 dioxygenase (IDO), increased significantly in cAD-MSCs that were cocultured with leukocytes; however, the production of PGE2 and IDO showed different kinetics, and leukocyte proliferation was effectively restored by PGE2 and IDO inhibitors. Taken together, these results indicate that the immunomodulatory effects of cAD-MSCs are associated with soluble factors (TGF-beta, HGF, PGE2, and IDO). Therefore, it is suggested that cAD-MSCs have a potential therapeutic use in the treatment of immune-mediated disease.

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Although the pharmacology and clinical application of water extracts of Ganoderma lucidum have been extensively documented, little is known regarding its alcohol extract. In the present study, the anti-tumor effect of an alcohol extract of Ganoderma lucidum was investigated using MCF-7 cells. We found that the alcohol extract of Ganoderma lucidum inhibited cell proliferation in a dose-and time-dependent manner, which might be mediated through up-regulation of p21/Waf1 and down-regulation of cyclin D1. Furthermore, this compound can directly induce apoptosis in MCF-7 cells, which might be mediated through up-regulation of a pro-apoptotic Bax protein and not by the immune system. Our findings suggest that there are multiple mechanisms underlying the anti-tumor effects of Ganoderma lucidum. © 2002 Wiley-Liss, Inc. Key words: ganoderma lucidum; breast cancer; cell cycle; apoptosis An increasing number of natural occurring chemical compounds have been identified to be potent in the treatment of various human diseases including cancer. 1-4 Many of these substances are found in oriental herbs or plants. Recently, some chemopreventive extracts of herbs or plants have been shown to be anti-tumorigenic. [5][6][7][8] Carcinogenesis is a multistage or multimechanism process, involving the irreversible alteration of a stem cell (the "initiation" phase), followed by the clonal proliferation of the initiated stem cell (the "promotion" phase), from which the acquisition of the invasive and metastatic phenotypes are generated (the "progression" phase). 9 Cancer prevention or therapy may be accomplished at different steps of this process by different mechanisms. Mixed extract of herbs or plants might contain different chemopreventive chemotherapeutic compounds with more than one mechanism of action, thus possessing a combination of different chemopreventive or chemotherapeutic effects. It is therefore very attractive and important to identify combination effects of mixed extract of herbs or plants.Ganoderma lucidum, an oriental fungus, has been widely used as a medical drug or health-promotion product in China and other Asian countries. The fruiting bodies and cultured mycelia of Ganoderma lucidum have been demonstrated to possess anti-tumor activities, 10 -18 immunomodulatory activities, 19 -20 and neuroactive effects. 21 Although numerous studies on the effects of water extracts of GL have been reported, 10 -16 little is known regarding its alcohol extracts. It has been reported that the alcohol extract of Ganoderma lucidum can induce cell cycle arrest at transition from G1 to S phase in HeLa-cells 17 This study was designed to further investigate the anti-tumor effects of alcohol extracts of Ganoderma lucidum and elucidate the potential mechanisms using an in vitro system. We found that the alcohol extract of Ganoderma lucidum was able to induce cell cycle arrest at G1 phase and induce apoptosis in MCF-7 cells in a time-dependent manner. The mechanisms might be mediated through up-regulation of the expression of p21/Waf1-a...

HDAC activity is essential for maintaining the self-renewal and pluripotency of MSCs.