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Hepatitis B virus (HBV) generates large amounts of complete and incomplete viral particles. Except for the virion, which acts as infectious particles, the function of those particles remains elusive. Extracellular vesicles (EVs) have been revealed to have biological functions. The EVs which size are less than 100 nm in diameter, were collected from HBV infected-patients. These vesicles contain, complete and incomplete virions, and exosomes, which have been recently shown to be critical as intercellular communicators. Here, the effects of the exosome, the complete, and the incomplete particles on the target cells were investigated. These particles are endocytosed by monocyte/macrophages and function primarily to upregulate PD-L1. The functions and composition of the EVs were affected by nucleotide reverse transcriptase inhibitors (NRTIs), suggesting that the EVs are involved in the pathogenesis of HBV hepatitis and clinical course of those patients treated by NRTIs.

The circulating levels of β-carotene are modulated not only by sex, but also by autosomal gene variations and fruit intake. The aim of this study was to investigate the interactions between β-carotene metabolism-related gene single nucleotide polymorphisms (SNPs; genetic factors) and nutrient intake (environmental factors) relating to their effects on circulating β-carotene. The serum concentrations of β-carotene and the habitual food intake of 92 healthy Japanese adults were examined. All subjects were genotyped for three common SNPs: rs6564851 in the β-carotene 15,15'-oxygenase 1 (BCO1) gene, rs2278986 in the scavenger receptor class B member 1 (SCARB1) gene and rs362090 in the intestine-specific homeobox (ISX) gene. Univariate analysis revealed that the circulating β-carotene levels were significantly higher in rs6564851 GG homozygotes (p = 0.003). Additionally, the daily intake of β-cryptoxanthin was positively associated with the circulating β-carotene levels in female GG homozygotes of rs6564851 (p = 0.023), and the daily intake of α- and β-carotenes, and β-cryptoxanthin was significantly lower in female rs6564851 T allele carries than in female GG homozygotes (p = 0.009, 0.008, 0.009, respectively). The present study apparently indicates that higher circulating β-carotene levels in female rs6564851 GG homozygotes depend on carotenoid intake.

Histone-modifiable lysine-specific demethylase-1 (LSD1/KDM1A) is an oncoprotein upregulated in cancers, including hepatoma. We previously reported that the hepatoma-preventive geranylgeranoic acid (GGA) inhibits KDM1A at the same IC as that of the clinically used tranylcypromine. Here, we report that these inhibitors induce the cytoplasmic translocation of nuclear KDM1A in a human hepatoma-derived cell line. Immunofluorescence studies revealed that KDM1A was cytoplasmically localized in HuH-7 cells 3 h after GGA or tranylcypromine addition. However, GGA did not affect the subcellular localization of another histone lysine-specific demethylase, KDM5A. This suggests that GGA-induced translocation is KDM1A specific. These data demonstrate, for the first time, that KDM1A inhibitors specifically induce the cytoplasmic translocation of nuclear KDM1A.

Runx2 plays essential roles in osteoblast differentiation and chondrocyte maturation. Runx2 in the perichondrium has been reported to inhibit chondrocyte maturation through Fgf18 induction. To further investigate the functions of Runx2 in the perichondrium, we generated Runx2fl/−Cre mice by crossing Runx2fl/+, Runx2+/−, and 2.3-kb Col1a1 Cre mice and compared them with Runx2fl/− mice at E15.5, when the endochondral bones were cartilaginous. Skeletal preparation of the upper limbs in Runx2fl/−Cre mice showed reduced mineralization of the humerus and scapula, and histological analysis of the femurs showed delays in the terminal differentiation of chondrocytes, as indicated by the absence of mineralization and Spp1 expression in the cartilage and osteoblast differentiation in the perichondrium, compared to those in Runx2fl/− mice. mRNA sequence analysis showed that the expression of Nell1, which encodes a secreted protein that enhances chondrocyte maturation, in Runx2fl/−Cre femurs was more than two-fold lower than that in Runx2fl/− femurs. Nell1 expression was reduced in the perichondrium of Runx2fl/−Cre femurs compared to that in Runx2fl/− femurs. Nell1 expression was upregulated by Runx2 overexpression and downregulated by Runx2 siRNA. These findings indicate that Runx2 in perichondrial osteoblasts enhances the terminal differentiation of chondrocytes by inducing Nell1 expression.

Runx2 is an essential transcription factor for osteoblast differentiation and chondrocyte maturation. The spatiotemporal expression of Runx2 is regulated by enhancers. We previously identified a 1.3 kb osteoblast-specific enhancer; however, mice with this deletion showed no phenotypes. A 0.8 kb conserved region detected near the 1.3 kb enhancer did not exhibit enhancer activity in reporter assays, whereas four tandem repeats of 452 bp (452 × 4) containing the most conserved region of 0.8 kb induced strong reporter activity in chondrocyte cell lines. However, chondrocytes of enhanced green fluorescent protein (EGFP) reporter mice using 452 × 4 did not express EGFP. When 452 × 4 was combined with the 1.3 kb enhancer, hypertrophic chondrocytes highly expressed EGFP. Moreover, the 0.8 kb region combined with the 1.3 kb enhancer induced EGFP expression in prehypertrophic and hypertrophic chondrocytes. The deletion of both the 1.3 kb enhancer and the 0.8 kb conserved region slightly reduced Runx2 expression in the limbs. However, neither homozygous nor heterozygous deletions in the Runx2+/− background showed phenotypes. The 0.8 kb conserved region itself lacked enhancer activity, but when combined with the 1.3 kb enhancer, EGFP expression was induced in chondrocytes with a similar expression pattern to Runx2. Therefore, the 0.8 kb conserved region has a novel function as a subenhancer.

The circulating levels of [beta]-carotene are modulated not only by sex, but also by autosomal gene variations and fruit intake. The aim of this study was to investigate the interactions between [beta]-carotene metabolism-related gene single nucleotide polymorphisms (SNPs; genetic factors) and nutrient intake (environmental factors) relating to their effects on circulating [beta]-carotene. The serum concentrations of [beta]-carotene and the habitual food intake of 92 healthy Japanese adults were examined. All subjects were genotyped for three common SNPs: rs6564851 in the [beta]-carotene 15,15'-oxygenase 1 (BCO1) gene, rs2278986 in the scavenger receptor class B member 1 (SCARB1) gene and rs362090 in the intestine-specific homeobox (ISX) gene. Univariate analysis revealed that the circulating [beta]-carotene levels were significantly higher in rs6564851 GG homozygotes (p = 0.003). Additionally, the daily intake of [beta]-cryptoxanthin was positively associated with the circulating [beta]-carotene levels in female GG homozygotes of rs6564851 (p = 0.023), and the daily intake of [alpha]- and [beta]-carotenes, and [beta]-cryptoxanthin was significantly lower in female rs6564851 T allele carries than in female GG homozygotes (p = 0.009, 0.008, 0.009, respectively). The present study apparently indicates that higher circulating [beta]-carotene levels in female rs6564851 GG homozygotes depend on carotenoid intake.

Histone-modifiable lysine-specific demethylase-1 (LSD1/KDM1A) is often upregulated in many cancers, including hepatoma, and is regarded as oncoprotein. We previously reported that the hepatoma-preventive geranylgeranoic acid (GGA) inhibits KDM1A activity at the same IC50 as that of the clinically used drug tranylcypromine, a verified inhibitor of KDM1A. Here, we report that these inhibitors induced cytoplasmic translocation of nuclear KDM1A in a human hepatoma-derived cell line. Immunofluorescence studies revealed cytoplasmic localization of KDM1A, 3 h after addition of GGA or tranylcypromine in HuH-7 cells. Geranylgeraniol and all-trans retinoic acid were both unable to induce translocation of nuclear KDM1A, whereas farnesoic acid showed the weak activity. Furthermore, GGA did not affect subcellular localization of another histone lysine-specific demethylase, KDM5A. This suggests that the inhibitor-induced translocation of nuclear KDM1A to the cytoplasm is specific for KDM1A. These data demonstrate for the first time that KDM1A inhibitors specifically induce the cytoplasmic translocation of nuclear KDM1A.