Chondrosarcoma and Peroxisome Proliferator-Activated Receptor

Induction of differentiation and apoptosis in cancer cells by ligands of PPARγ is a novel therapeutic approach to malignant tumors. Chondrosarcoma (malignant cartilage tumor) and OUMS-27 cells (cell line established from grade III human chondrosarcoma) express PPARγ. PPARγ ligands inhibited cell proliferation in a dose-dependent manner, and induced apoptosis of OUMS-27. The higher-grade chondrosarcoma expressed a higher amount of antiapoptotic Bcl-xL in vivo. The treatment of OUMS-27 by 15d-PGJ2, the most potent endogenous ligand for PPARγ, downregulated expression of Bcl-xL and induced transient upregulation of proapoptotic Bax, which could accelerate cytochrome c release from mitochondria to the cytosol, followed by induction of caspase-dependent apoptosis. 15d-PGJ2 induced the expression of CDK inhibitor p21 protein in human chondrosarcoma cells, which appears to be involved in the mechanism of inhibition of cell proliferation. These findings suggest that targeted therapy with PPARγ ligands could be a novel strategy against chondrosarcoma

Inhibition of activin/nodal signalling is necessary for pancreatic differentiation of human pluripotent stem cells

Peer reviewedPublisher PD

Devil's staircase transition of the electronic structures in CeSb

Solids with competing interactions often undergo complex phase transitions with a variety of long-periodic modulations. Among such transition, devil's staircase is the most complex phenomenon, and for it, CeSb is the most famous material, where a number of the distinct phases with long-periodic magnetostructures sequentially appear below the Neel temperature. An evolution of the low-energy electronic structure going through the devil's staircase is of special interest, which has, however, been elusive so far despite the 40-years of intense researches. Here we use bulk-sensitive angle-resolved photoemission spectroscopy and reveal the devil's staircase transition of the electronic structures. The magnetic reconstruction dramatically alters the band dispersions at each transition. We moreover find that the well-defined band picture largely collapses around the Fermi energy under the long-periodic modulation of the transitional phase, while it recovers at the transition into the lowest-temperature ground state. Our data provide the first direct evidence for a significant reorganization of the electronic structures and spectral functions occurring during the devil's staircase.Comment: 22 pages, 5 figure

Dkk4 and Eda Regulate Distinctive Developmental Mechanisms for Subtypes of Mouse Hair

The mouse hair coat comprises protective “primary” and thermo-regulatory “secondary” hairs. Primary hair formation is ectodysplasin (Eda) dependent, but it has been puzzling that Tabby (Eda-/y) mice still make secondary hair. We report that Dickkopf 4 (Dkk4), a Wnt antagonist, affects an auxiliary pathway for Eda-independent development of secondary hair. A Dkk4 transgene in wild-type mice had no effect on primary hair, but secondary hairs were severely malformed. Dkk4 action on secondary hair was further demonstrated when the transgene was introduced into Tabby mice: the usual secondary follicle induction was completely blocked. The Dkk4-regulated secondary hair pathway, like the Eda-dependent primary hair pathway, is further mediated by selective activation of Shh. The results thus reveal two complex molecular pathways that distinctly regulate subtype-based morphogenesis of hair follicles, and provide a resolution for the longstanding puzzle of hair formation in Tabby mice lacking Eda

A Crucial Role of Activin A-Mediated Growth Hormone Suppression in Mouse and Human Heart Failure

Infusion of bone marrow-derived mononuclear cells (BMMNC) has been reported to ameliorate cardiac dysfunction after acute myocardial infarction. In this study, we investigated whether infusion of BMMNC is also effective for non-ischemic heart failure model mice and the underlying mechanisms. Intravenous infusion of BMMNC showed transient cardioprotective effects on animal models with dilated cardiomyopathy (DCM) without their engraftment in heart, suggesting that BMMNC infusion improves cardiac function via humoral factors rather than their differentiation into cardiomyocytes. Using conditioned media from sorted BMMNC, we found that the cardioprotective effects were mediated by growth hormone (GH) secreted from myeloid (Gr-1(+)) cells and the effects was partially mediated by signal transducer and activator of transcription 3 in cardiomyocytes. On the other hand, the GH expression in Gr-1(+) cells was significantly downregulated in DCM mice compared with that in healthy control, suggesting that the environmental cue in heart failure might suppress the Gr-1(+) cells function. Activin A was upregulated in the serum of DCM models and induced downregulation of GH levels in Gr-1(+) cells and serum. Furthermore, humoral factors upregulated in heart failure including angiotensin II upregulated activin A in peripheral blood mononuclear cells (PBMNC) via activation of NFκB. Similarly, serum activin A levels were also significantly higher in DCM patients with heart failure than in healthy subjects and the GH levels in conditioned medium from PBMNC of DCM patients were lower than that in healthy subjects. Inhibition of activin A increased serum GH levels and improved cardiac function of DCM model mice. These results suggest that activin A causes heart failure by suppressing GH activity and that inhibition of activin A might become a novel strategy for the treatment of heart failure