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OBJECTIVEGiven the pleiotropic effect of eicosapentaenoic acid (EPA), it is interesting to know whether EPA is capable of improving obesity. Here we examined the anti-obesity effect of EPA in mice with two distinct models of obesity.RESEARCH DESIGN AND METHODSMale C57BL/6J mice were fed a high-fat/high-sucrose diet (25.0% [w/w] fat, 32.5% [w/w] sucrose) (HF/HS group) or a high-fat diet (38.1% [w/w] fat, 8.5% [w/w] sucrose) (HF group) for 4–20 weeks. A total of 5% EPA was administered by partially substituting EPA for fat in the HF/HS + EPA and HF + EPA groups.RESULTSBoth the HF/HS and HF groups similarly developed obesity. EPA treatment strongly suppresses body weight gain and obesity-related hyperglycemia and hyperinsulinemia in HF/HS-fed mice (HF/HS + EPA group), where hepatic triglyceride content and lipogenic enzymes are increased. There is no appreciable effect of EPA on body weight in HF-fed mice (HF + EPA group) without enhanced expression of hepatic lipogenic enzymes. Moreover, EPA is capable of reducing hepatic triglyceride secretion and changing VLDL fatty acid composition in the HF/HS group. By indirect calorimetry analysis, we also found that EPA is capable of increasing energy consumption in the HF/HS + EPA group.CONCLUSIONSThis study is the first demonstration that the anti-obesity effect of EPA in HF/HS-induced obesity is associated with the suppression of hepatic lipogenesis and steatosis. Because the metabolic syndrome is often associated with hepatic lipogenesis and steatosis, the data suggest that EPA is suited for treatment of the metabolic syndrome.

Progenitors that can transdifferentiate into cells with hepatic or pancreatic phenotypes can be isolated from experimentally injured salivary glands of rodents. In this study, we isolated progenitors from "uninjured" adult human salivary glands by fluorescence-activated cell sorting using anti-CD49f and anti-Thy-1 antibodies. The sorted cells that were contained in the CD49f+/Thy-1+ fraction showed good proliferation on type I collagen. Single purified progenitor cells in plate culture expressed intracellular laminin, CD49f, Thy-1, and NGF receptor p75 (p75(NGFR)). Immunohistological analysis revealed the expression of Thy-1 and p75(NGFR) in stromal cells in the periductal area of the salivary gland. Under overconfluent conditions in plate culture, cell clusters containing insulin and glucagon-positive cells were occasionally formed. In order to produce differentiated cell clusters with uniform quality, we used a spherical culture system. Autonomous differentiation of cells in clusters into insulin-positive cells was induced in the spherical culture system. We measured C-peptide to estimate the endogenously produced insulin content. The C-peptide content of the spheroid bodies was low (3.5 ng/mg of protein), and they simultaneously expressed the early islet differentiation factor Nkx6.1, proendocrine gene neurogenin3, and ductal cell marker cytokeratin19. The progenitors existing in the interstitium of the salivary gland were able to transdifferentiate into cells with a pancreatic endocrine phenotype.

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Small interfering RNAs (siRNAs) are expected to have a medical application in human therapy as drugs with a high specificity for their molecular target mRNAs. RecQL1 DNA helicase in the human RecQ helicase family participates in DNA repair and recombination pathways in the cell cycle of replication. Silencing the RecQL1 expression by RecQL1-siRNA induces mitotic death in vitro specifically in growing cancer cells. By contrast, the same RecQL1 silencing does not affect the growth of normal cells, emphasizing that RecQL1 helicase is an ideal molecular target for cancer therapy. In this study, we show that local and systemic administration of RecQL1-siRNA mixed with polyethyleneimine polymer or cationic liposomes prevented cancer cell proliferation in vivo in mouse models of cancer without noticeable adverse effects. The results indicate that RecQL1-siRNA in a complex with a cationic polymer is a very promising anticancer drug candidate, and that in particular, RecQL1-siRNA formulated with a cationic liposome has an enormous potential to be used by intravenous injection for therapy specific for liver cancers, including metastasized cancers from the colon and pancreas. (Cancer Sci 2008; 99: 1227-1236) H uman RecQL1 DNA helicase (RecQL1), a member of the RecQ helicase family, participates in the maintenance of genomic integrity and is highly up-regulated in rapidly growing cells, including various cancers and transformed cells.(1-5)RecQL1 unwinds specific DNA in vitro ATP-dependently and can increase base matching ATP-independently. (6,7) It is assumed to participate in the mismatch repair pathway in vivo because it binds to the incision activity of human EXO1 and the mismatch repair recognition complex MSH2/6.(8) Also, RecQL1 acts as an enzyme that resolves Holliday junctions during cell proliferation. (9) Consequently, down-regulation of RecQL1 expression in HeLa cells by RNA interference (RNAi) increases sister chromatid exchanges resulting from unprocessed Holliday junction structures, (10) . Although RecQL1-deficient mice show no apparent phenotypic differences when compared with wild-type mice, embryonic fibroblasts from RecQL1-deficient mice are sensitive to ionizing radiation (11) (and our unpublished data Sakamoto et al. 1999). All these findings collectively showed that RecQL1 suppresses chromosomal instability by participating in DNA repair associated with cell proliferation, but its function seems to be nonessential and complemented by other cellular repair system(s).Silencing RecQL1 in cancer cells by RNAi with siRNA induces mitotic catastrophe and death in a wide range of cancer cells that have defects in the cell cycle checkpoint system.(12) By contrast, the same silencing does not cause mitotic death in growing normal cells that have a competent checkpoint system, even though their cell cycles slowed down. To test the efficacy of RecQL1-siRNA in vivo, we previously studied the multicellular cancer spheroids system, a three dimensional (3-D) model that uses human hepatocarcinoma HuH-7 cell lines to m...

A new cytotoxic compound, brasilibactin A (1), has been isolated from the actinomycete Nocardia brasiliensis IFM 0995, and the structure was elucidated on the basis of spectroscopic data and chemical means.