The Effects of Ischemia and Hyperoxygenation on Hair Growth and Cycle.

Alopecia has several causes, but its relationship with ischemia/hypoxia has not yet been investigated in detail. In this study, we studied the changes of hair follicles induced by ischemia and potential effects of normobaric hyperoxygenation (NBO) on the hair cycle and growth. We found that skin ischemia reduced hair growth rate, hair shaft size, and its pigmentation in the anagen phase of mice, which may reflect an aspect of pathophysiology of hair loss (alopecia) and depigmentation (gray/white hairs). Hyperoxygenation increased hair growth rate in organ culture of both human and murine hair follicles. Systemic NBO promoted hair growth in early anagen and mid-anagen, and delayed catagen onset in mice. However, telogen-to-anagen transition was not affected by NBO as far as non-ischemic skin is concerned. The results of this study indicated that the hair follicle is very sensitive to oxygen tension and oxygen tension affects the regulation of hair growth and cycle in vitro and in vivo. It was suggested that systemic NBO can be safely applied for a long period and can be a noninvasive therapeutic approach to alter hair growth and cycle by manipulating the microenvironment of hair follicles.

A mouse with humanized liver as an animal model for predicting drug effects and for studying hepatic viral infection: where to next?

INTRODUCTION: The mouse is a common model used in evaluating drug metabolism and hepatitis infectivity. However, these models have limited value due to species difference in hepatic functions, leading to the creation of the chimeric mouse 12 years ago. These models were unique in that their hepatocytes had been replaced with human (hu) hepatocytes (dubbed the 'first-generation chimeric mouse'). Since then, the chimeric mouse has become a practical tool for this area of studies. However, some shortcomings have also been recognized. One major shortcoming is that the mouse cannot mimic hu-liver diseases due to immunodeficiency and also it is unable to provide sufficient amounts of blood for analysis compared to the rat. There are also issues around donor-to-donor variability of hu-hepatocytes such as variable engraftment efficiency. AREAS COVERED: This review provides the current status of the first-generation chimeric mouse. Furthermore, the authors review studies intended to create a 'second-generation of the chimeric mouse' in which inflammation/immune-response cells as well as hepatocytes are humanized. A brief comment is also made on studies aiming at producing chimeric rats. Finally, the authors consider induced pluripotent stem cells (iPS cells) as new sources of hu-hepatocytes. EXPERT OPINION: The authors believe that the current rapid progress in the field of biotechnology should enable us to create a mouse model with a humanized liver that is made by iPS-derived hu-hepatocytes and hu-immune cells. This development will provide researchers with a model that will be able to effectively mimic human liver disease under experimental conditions.

Characterization of histone lysine-specific demethylase in relation to thyroid hormone-regulated anuran metamorphosis.

The thyroid hormone receptor (THR) is a member of the nuclear transcription factor and plays a central role in regulating anuran metamorphosis. Previous studies with mammalian cells have suggested that THR is involved in chromatin remodeling through histone methylation. In the present study, we cloned cDNA of lysine-specific demethylase gene, xLSD1, from Xenopus laevis and examined its expression in relation to metamorphosis. Overexpression of xLSD1 in A6 cells, a Xenopus laevis cell line, resulted in the decrease of methylation status of lysine residues of histone H3, indicating that the protein of cloned xLSD1 was functionally active. The expression of LSD1 at mRNA levels was up-regulated in the body skin and the intestine during natural and thyroid hormone-induced metamorphosis. Larval epidermal basal cells and intestinal epithelial cells at the premetamorphic stage were identified as the xLSD1-expressing cells. At the metamorphic climax stage the progenitor cells of adult epidermal basal cells also expressed xLSD1, whereas those of the adult intestinal epithelial cells did not. We propose that LSD1 participates in the regulation of metamorphosis through THR- or another transcriptional factor-induced chromatin remodeling.

Inchinkoto, a herbal medicine, and its ingredients dually exert Mrp2/MRP2-mediated choleresis and Nrf2-mediated antioxidative action in rat livers.

Inchinkoto (ICKT), a herbal medicine, has been recognized in Japan and China as a "magic bullet" for jaundice. To explore potent therapeutic agents for cholestasis, the effects of ICKT or its ingredients on multidrug resistance-associated protein 2 (Mrp2/ MRP2)-mediated choleretic activity, as well as on antioxidative action, were investigated using rats and chimeric mice with livers that were almost completely repopulated with human hepatocytes. Biliary excretion of Mrp2 substrates and the protein mass, subcellular localization, and mRNA level of Mrp2 were assessed in rats after 1-wk oral administration of ICKT or genipin, a major ingredient of ICKT. Administration of ICKT or genipin to rats for 7 days increased bile flow and biliary excretion of bilirubin conjugates. Mrp2 protein and mRNA levels and Mrp2 membrane densities in the bile canaliculi and renal proximal tubules were significantly increased in ICKT- or genipin-treated rat livers and kidneys. ICKT and genipin, thereby, accelerated the disposal of intravenously infused bilirubin. The treatment also increased hepatic levels of heme oxygenase-1 and GSH by a nuclear factor-E2-related factor (Nrf2)-dependent mechanism. Similar effects of ICKT on MRP2 expression levels were observed in humanized livers of chimeric mice. In conclusion, these findings provide the rationale for therapeutic options of ICKT and its ingredients that should potentiate bilirubin disposal in vivo by enhancing Mrp2/MRP2-mediated secretory capacities in both livers and kidneys as well as Nrf2-mediated antioxidative actions in the treatment of cholestatic liver diseases associated with jaundice.

Two-dimensional IgE-binding spectrum of Japanese cedar (Cryptomeria japonica) pollen allergens.

BACKGROUND: Japanese cedar (Cryptomeria japonica) pollen is one of the most prevalent sources of the allergens that elicit rhinitis and conjunctivitis. Only Cry j 1 and Cry j 2 have been well characterized as the major allergens of this pollen. OBJECTIVES: The aims of this study were to complete the repertoire of C. japonica pollen allergens, to investigate their variability with respect to IgE-reactive patterns and to identify the isoforms of Cry j 1 and Cry j 2 by proteome analysis. METHODS: Proteins in C. japonica pollen separated on two-dimensional (2-D) polyacrylamide gel electrophoresis were immunodetected with IgE in sera of 40 subjects allergic to C. japonica pollen. Mass fingerprinting was used to elucidate the diversity of the major allergens. RESULTS: 2-D immunolabeling with individual patients' sera showed the distinguishable IgE-binding patterns inlaid with 4-87 spots from a total of 131 IgE-binding protein spots. At least 12 Cry j 1 (27.5-75% of IgE-binding frequency) and 3 Cry j 2 (32.5-40%) isoforms were localized. In total, 31 spots were found to be more reactive than the highest IgE-reactive isoform of Cry j 2. CONCLUSIONS: The proteomics approaches showed great interindividual variation of IgE-binding patterns to C. japonica proteins and contributed to the repertoire of numerous C. japonica allergens other than Cry j 1 and Cry j 2. Protein microsequencing demonstrated more complicated multiplicity in Cry j 1 than previously known and new isoforms in Cry j 2.

Thyroid hormone regulation of a transcriptional coactivator in Xenopus laevis: implication for a role in postembryonic tissue remodeling.

Thyroid hormone (TH) affects biological processes by regulating gene transcription through TH receptors (TRs). In the presence of TH, TR activates target gene transcription by recruiting one or more transcription coactivators belonging to diverse groups. Here, we demonstrate that during TH-dependent anuran metamorphosis, one such coactivator gene, the Xenopus laevis homolog of human Trip7, is up-regulated by TH. Kinetic studies suggest that Xenopus Trip7 is most likely induced indirectly by TH in a tissue-dependent manner. In the intestine, which undergoes extensive remodeling as the animal changes from being herbivorous to carnivorous, Trip7 is expressed at high levels during but not before or after metamorphosis. It is also up-regulated in other growing or remodeling tissues such as the brain and limb but not in degenerating tadpole tail skin. By using frog oocyte as a model, we show that Trip7 influences basal transcription in a chromatin structure-dependent manner but enhances the function of liganded TR regardless of the chromatin structure of the target promoter. In vitro studies indicate that Trip7 interacts directly with TR. These results suggest that during Xenopus metamorphosis, TH up-regulates, albeit indirectly, Trip7 to enhance TR function during larval-to-adult tissue transformation.