Oral administration of an HSP90 inhibitor, 17-DMAG, intervenes tumor-cell infiltration into multiple organs and improves survival period for ATL model mice.

In the peripheral blood leukocytes (PBLs) from the carriers of the human T-lymphotropic virus type-1 (HTLV-1) or the patients with adult T-cell leukemia (ATL), nuclear factor kappaB (NF-κB)-mediated antiapoptotic signals are constitutively activated primarily by the HTLV-1-encoded oncoprotein Tax. Tax interacts with the I κB kinase regulatory subunit NEMO (NF-κB essential modulator) to activate NF-κB, and this interaction is maintained in part by a molecular chaperone, heat-shock protein 90 (HSP90), and its co-chaperone cell division cycle 37 (CDC37). The antibiotic geldanamycin (GA) inhibits HSP90's ATP binding for its proper interaction with client proteins. Administration of a novel water-soluble and less toxic GA derivative, 17-dimethylaminoethylamino-17-demethoxygeldanamycin hydrochloride (17-DMAG), to Tax-expressing ATL-transformed cell lines, C8166 and MT4, induced significant degradation of Tax. 17-DMAG also facilitated growth arrest and cellular apoptosis to C8166 and MT4 and other ATL cell lines, although this treatment has no apparent effects on normal PBLs. 17-DMAG also downregulated Tax-mediated intracellular signals including the activation of NF-κB, activator protein 1 or HTLV-1 long terminal repeat in Tax-transfected HEK293 cells. Oral administration of 17-DMAG to ATL model mice xenografted with lymphomatous transgenic Lck-Tax (Lck proximal promoter-driven Tax transgene) cells or HTLV-1-producing tumor cells dramatically attenuated aggressive infiltration into multiple organs, inhibited de novo viral production and improved survival period. These observations identified 17-DMAG as a promising candidate for the prevention of ATL progression.

Sex differences in energy metabolism in pre-pubescent, early pubescent and adult rats.

OBJECTIVE: This study was intended to investigate sex differences in response to a high fat (HF) diet at three stages, pre-puberty, early puberty, and adulthood. METHODS: Body weight, energy intake, glucose, insulin, and leptin concentrations were measured in male and female rats that were fed either a HF or a control chow during each stage of development. The sex hormones of adult rats were also examined. In addition, metabolic factors of male rats pair-fed with females were evaluated. RESULTS: At pre-puberty, the average body weight of pups born to a HF dam exceeded that of the control, whereas there were no significant differences in body weight between males and females. During early puberty and among 15-wk-old rats, males exhibited greater weight gain with higher energy intake than did females. During all three stages, HF rats exhibited significant increases in body weight, insulin and leptin concentrations. Estradiol levels of females were higher than those of males, and those of the HF groups were significantly lower than the control groups. Although the body weight gain in male rats pair-fed with females exceeded that of the females, the insulin and leptin levels of pair-fed HF males decreased to the control levels. CONCLUSION: HF male rats became obese earlier than HF females. This result may be the result of differences in estradiol levels between males and females. The decline of insulin and leptin levels in pair-fed male groups indicates that caloric restriction among male rats could reduce the incidence of metabolic diseases.

The chondrogenic repair response of undifferentiated mesenchymal cells in rat full-thickness articular cartilage defects.

OBJECTIVE: The aim of this study is to develop a rat model of full-thickness articular cartilage defects that is suitable for detailed molecular analyses of the regenerative repair of cartilage. MATERIALS AND METHODS: The V-shaped full-thickness defects (width: 0.7 mm; depth: 0.8 mm; and length: 4mm) were created in the femoral patellar groove of 6 weeks old male rats using a custom-built twin-blade device. Prior to starting the repair experiments, our device was examined for its accuracy and reliability in generating defects. Then, the time course of the repair response in these cartilage defects was examined using a semi-quantitative histological grading scale. The expression of chondrogenic differentiation markers in the reparative regions was examined with immunohistochemistry and in situ hybridization. RESULTS: Our device creates full-thickness articular cartilage defects uniformly. In these defects, undifferentiated mesenchymal cells filled the defect cavities (4 days) and initiated chondrogenic differentiation at the center of the defect (7 days). Cartilage formation was observed in the same region (2 weeks). Finally, hyaline-like articular cartilage and subchondral bone layers were reconstituted in their appropriate locations (4 weeks). CONCLUSIONS: We have successfully developed a rat model containing identically sized full-thickness defects of articular cartilage that can undergo chondrogenic repair in a reproducible fashion.