a b s t r a c tDemyelination was induced by two weeks cuprizone treatment. Rats of +ve control and triiodothyronine (T3) then received three subcutaneous injections of either saline or T3 day after day and sacrificed at the end of the third and fifth weeks. Animals in −ve control group received only standard rodent chow. After one week of cuprizone withdrawal the corpus callosum in +ve control and T3 treated rats was still demyelinated as revealed by MBP immunohistochemistry. The assay of PLP gene showed significant increase of T3 treated group compared to both the −ve control and +ve control groups. After three weeks, significant improvement in myelination was detected in T3-treated group compared to +ve control as detected by both MBP immunohistochemistry and electron microscopy. After one week of cuprizone withdrawal, PDGFR␣ positive cells and gene expression showed significant increase in +ve control and T3-treated groups as compared to −ve control with insignificant difference in between the former two groups. After three weeks of cuprizone withdrawal, PDGFR␣ positive cells in T3-treated and +ve control groups decreased to the control levels. These results suggest that T3 was effective in improving remyelination when administered during acute phase and might direct progenitor lineage toward oligodendrocytes.

Targeting of endothelin system genes is a promising strategy in cancer therapy. The modulation of these genes was explored in a model of colorectal cancer (CRC) liver metastasis and in a panel of CRC tumor cell lines that were exposed to the demethylating agent decitabine. The CC531 rat model mimicking CRC liver metastasis was used for tumor cell re-isolation and analysis of the endothelin system genes and DNA methyltransferases (DNMTs) by microarray. To mimic the effects caused by methylation changes, a panel of seven CRC cell lines was treated with the demethylating agent decitabine. Three genes of the endothelin system were potently modulated at messenger RNA (mRNA) level in rat CC531 cells during liver colonization. The concomitant decrease of two DNMTs suggested an influence from altered methylation. Changes in gene expression were also accomplished by exposure of CRC cells to the demethylating agent decitabine, when using daily low concentrations for 3 days, with minimal cytotoxic effects. Sensitive human SW480 cells showed an almost 100fold upregulation of endothelin-1 mRNA compared to untreated cells. This, however, was different in LS174T cells, which showed no significant increase in gene expression although the methylation levels were significantly decreased at a variety of corresponding loci. We suggest that the mechanism induced by methylation on gene expression in metastatic CRC cells can be compromised. The results question the overall success of treating metastatic CRC by methylation inhibitors.

BackgroundOval cells, specific liver progenitors, are activated in response to injury. The human umbilical cord blood (hUCB) is a possible source of transplantable hepatic progenitors and can be used in cases of severe liver injury. We detected the effect of hUCB stem cell transplantation on natural response of oval cells to injury.MethodsTwenty-four female albino rats were randomly divided into three groups: (A) control, (B) liver injury with hepatocyte block, and (C) hUCB transplanted group. Hepatocyte block was performed by administration of 2-acetylaminofluorene (2-AAF) for 12 days. CCL4 was administrated at day 5 from experiment start. Animals were sacrificed at 9 days post CCL4 administration, and samples were collected for biochemical and histopathological analysis. Oval cell response to injury was evaluated by the percentage of oval cells in the liver tissue and frequency of cells incorporated into new ducts.ResultsImmunohistochemical analysis of oval cell response to injury was performed. There was significant deviation in the hUCB-transplanted (4.9 ± 1.4) and liver injury groups (2.4 ± 0.9) as compared to control (0.89 ± 0.4) 9 days post injury. Detection of oval cell response was dependant on OV-6 immunoreactivity. For mere localization of cells with human origin, CD34 antihuman immunoreactivity was performed. There was no significant difference in endogenous OV-6 immunoreactivity following stem cell transplantation as compared to the liver injury group.ConclusionsIn vivo transplantation of cord blood stem cells (hUCB) does not interfere with natural oval cell response to liver injury.

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Endothelin system members including endothelin-1, endothelin-2, endothelin-3, endothelin receptors, and