Mutation signatures represent unique sequence footprints of somatic mutations resulting from specific DNA mutagenic and repair processes. However, their causal associations and the potential utility for genome research remain largely unknown. In this study, we performed PanCancer-scale correlative analyses to identify the genomic features associated with tumor mutation burdens (TMB) and individual mutation signatures. We observed that TMB was correlated with tumor purity, ploidy, and the level of aneuploidy, as well as with the expression of cell proliferation-related genes representing genomic covariates in evaluating TMB. Correlative analyses of mutation signature levels with genes belonging to specific DNA damage-repair processes revealed that deficiencies of NHEJ1 and ALKBH3 may contribute to mutations in the settings of APOBEC cytidine deaminase activation and DNA mismatch repair deficiency, respectively. We further employed a strategy to identify feature-driven, de novo mutation signatures and demonstrated that mutation signatures can be reconstructed using known causal features. Using the strategy, we further identified tumor hypoxia-related mutation signatures similar to the APOBEC-related mutation signatures, suggesting that APOBEC activity mediates hypoxia-related mutational consequences in cancer genomes. Our study advances the mechanistic insights into the TMB and signature-based DNA mutagenic and repair processes in cancer genomes. We also propose that feature-driven mutation signature analysis can further extend the categories of cancer-relevant mutation signatures and their causal relationships.
Purpose : Hyper IgM syndrome(HIGM) is characterized by severe recurrent bacterial infections with decreased serum levels of IgG, IgA, and IgE but elevated IgM levels. Recently, it has been classified into three groups; HIGM1, HIGM2 and a rare form of HIGM. HIGM1 is a X-linked form of HIGM and has now been identified as a T-cell deficiency in which mutations occur in the gene that encodes the CD40 ligand molecule. HIGM2 is an autosomal recessive form of HIGM. Molecular studies have shown that the mutation of HIGM2 is in the gene that encodes activation-induced cytidine deaminase(AID). Recently, another rare form of X-linked HIGM syndrome associated with hypohydrotic ectodermal dysplasia has been identified. We encountered a patient with a varient form of HIGM2. To clarify the cause of this form of HIGM, we evaluated the peripheral B cells of this patient. Methods : The lymphocytes of the patient were prepared from peripheral blood. B cells were immortalized with the infection of EBV. Cell cycle analysis was done with the immortalized B cells of the patient. Peripheral mononuclear cells were stained with monoclonal anti-CD40L antibody. Total RNA was extracted from the peripheral mononuclear cells. After RT-PCR, direct sequencing for CD40L gene and HuAID gene were done. Immunostainings of a lymph node for CD3, CD23, CD40, Fas-L, bcl-2, BAX were done. Results : The peripheral B cells of this patient showed normal expression of CD40L molecule and normal sequencing of CD40L gene, and also normal sequencing of AID gene. Interestingly, the peripheral B cells of this patient showed a decreased population of G2/mitosis phase in cell cycles which recovered to normal with the stimulation of IL-4. Conclusion : We suspect that the cause of increased serum IgM in this patient may be from a decrease of G2/mitosis phase of the peripheral B cells, which may be from the decreased production or secretion of IL-4. Therefore, this may be a new form of HIGM.
Park, Jung-Ae;Park, Cheol;Han, Min-Ho;Kim, Byung-Woo;Chung, Yoon-Ho;Choi, Yung-Hyun
Journal of Life Science
/
v.21
no.5
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pp.720-728
/
2011
Garlic (Allium sativum) has been used as a source food as well as a traditional folk medicine ingredient since ancient times. Aged black garlic is a type of fermented garlic and is expected to have stronger anticancer and antioxidant activities than raw garlic. However, the mechanisms of their inhibitory effects on adipocyte differentiation and adipogenesis are poorly understood. In the present study, the effects and mechanisms of water extracts of raw garlic (WERG) and aged black garlic (WEABG) on adipocyte differentiation and adipogenesis in 3T3-L1 preadipocytes were investigated. Treatment with WEABG significantly suppressed terminal differentiation of 3T3-L1 preadipocytes in a dose-dependent manner as confirmed by a decrease in lipid droplet number and lipid content through Oil Red O staining, however WERG had no such effect. In addition, WEABG reduced accumulation of cellular triglyceride, which is associated with a significant inhibition of key pro-adipogenic transcription factors including peroxisome proliferator-activated receptor ${\gamma}$ (PPAR${\gamma}$), cytidine-cytidine-adenosine-adenosine-thymidine (CCAAT)/enhancer binding proteins ${\alpha}$ (C/EBP${\alpha}$) and C/EBP${\beta}$. Taken together, these results provide important new insight that aged black garlic might inhibit adipogenesis by suppressing the pro-adipogenic transcription factors in 3T3-L1 preadipocytes, and further studies will be needed to identify the active compounds that confer the anti-obesity activity of aged black garlic.
Journal of the Korean Society of Food Science and Nutrition
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v.36
no.5
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pp.569-577
/
2007
The purpose of the present study was to propose some amendments on nutrient standard regulations of infant formula in Korea. For this purpose, we compared and analyzed the nutrient regulations of Korea, CODEX, U.S.A, Japan, EU, Australia and New Zealand. Some developing aspects of Korea's nutrient standard regulations for infant formula need to be examined as follows: firstly, both milk-based formula and soy-based formula standards would be unified into an infant formula, and the user of infant formula would be categorized for babies less than 6 month old. Secondly, nitrogen conversion factor of milk protein in the infant formula would be 6.38, which is the same as that of CODEX Revised Standard. Protein quantities could be differentiated by protein sources, and essential amino acids in human milk would be standardized according to protein contents. Thirdly, $\alpha$-linolenic acid, docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA) as essential fatty acids and trans fatty acid would be standardized in terms of the contents. Fourthly, it is recommended that the unit of vitamins and minerals would be changed from g/100 g to g/100 kcal, and individual vitamins and mineral would have their maximum values. Finally, 5 nucleotides (cytidine, uridine, adenosine, guanosine, inosine 5'-monophosphate) and fluoride would be required for the strengthening the immunity and the development of teeth, respectively. In conclusion, the scientific studies on amendment scheme of nutrient standard regulations of infant formula is very important to fortify nutritional completeness for Korean infants and young children.
Kim, Hyang Suk;Kwon, Da Hye;Cheon, Ji Min;Choi, Eun Ok;Kim, Ji Hyun;Han, Min Ho;Choi, Yung Hyun;Kim, Byung Woo;Hwang, Hye Jin
Journal of Life Science
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v.25
no.1
/
pp.62-67
/
2015
Myelophycus simplex Papenfuss is distributed over the northern Pacific and southern coast of Korea, and is a member of the brown algae family. The objective of this study was to investigate the effect of M. simplex methanol extract on adipocyte differentiation and adipogenesis in 3T3-L1 preadipocytes. Treatment with M. simplex methanol extract significantly suppressed terminal differentiation of 3T3-L1 preadipocytes in a dose-dependent manner, as confirmed by a decrease in lipid droplet content observed by Oil Red O staining. Also, the M. simplex methanol extract significantly suppressed the triglyceride content of 3T3-L1 preadipocytes in a dose-dependent manner. Treatment with 300 and $500{\mu}g/ml$ of M. simplex methanol extract caused a 42% and 76% reduction in lipid droplet content, respectively. In order to understand the anti-adipogenic effects of M. simplex methanol extract, the changes in the expression of several adipogenic transcription factors, including peroxisome proliferator-activated receptor (PPAR) ${\gamma}$-cytidine-cytidine-adenosine-adenosine-thymidine (CCAAT)/enhancer binding protein (C/EBP) ${\alpha}$ and ${\beta}$, were investigated using immunoblotting. M. simplex suppressed the expression of $PPAR{\gamma}$, $C/EBP{\alpha}$, and $C/EBP{\beta}$ proteins compared with control. Therefore, the results of this study suggest that M. simplex methanol extract inhibits adipocyte differentiation and thus may have applications as a potential source for an anti-obesity functional food agent.
Park, Jung Ae;Jin, Kyong-Suk;Oh, You Na;Hyun, Sook Kyung;Choi, Yung Hyun;Kwon, Hyun Ju;Kim, Byung Woo
Journal of Life Science
/
v.23
no.1
/
pp.69-78
/
2013
Vitis amurensis Rupreche, a sort of grape, grows naturally in Asian countries. It is known for important biological effects such as antioxidation, anti-inflammation, neuroprotection, and angiogenesis inhibition. Although its root is used as a traditional folk medicine in Korea, the root's biological activities are poorly studied. In the present study, the effects of V. amurensis root methanol extract (VARM) and its solvent fractions on adipocyte differentiation and adipogenesis in 3T3-L1 preadipocytes were investigated. The VARM significantly suppressed adipocyte differentiation, lipid accumulation, and the triglyceride (TG) content of 3T3-L1 preadipocytes in a dose-dependent manner, without cytotoxicity. To identify active molecules, the VARM was fractionated with a series of organic solvents including dichloromethane ($CH_2Cl_2$), ethyl acetate (EtOAc), and n-butanol (n-BuOH). All the fractions also showed inhibition of lipid accumulation in the 3T3-L1 preadipocytes. The $CH_2Cl_2$ fraction showed the most powerful anti-obesity effect through the modulation of cytidine-cytidine-adenosine-adenosinethymidine (CCAAT)/enhancer binding protein ${\alpha}$ ($C/EBP{\alpha}$), $C/EBP{\beta}$, peroxisome proliferator-activated receptor ${\gamma}$ ($PPAR{\gamma}$) gene and protein expression. Oleanolic acid was one of the main active compounds involved in the anti-obesity activity of the V. amurensis root. These results provide important new insight into the potential potent anti-adipogenic effect of the V. amurensis root and illustrate that one of the main compounds involved in this effect is oleanolic acid.
Bang, Keuk Soo;Chang, Young Nam;Jin, Jong Sik;Park, Sang A;Lim, Jae Soo;Park, Jeong Sub;Kim, Jong Sung;Lee, Jeong Ho
Korean Journal of Plant Resources
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v.28
no.1
/
pp.126-134
/
2015
Glycyrrhiza uralensis Fischer is one of the most commonly used herbs. Recently, the stem and leave of the plant have been interested in physiological activities because the aerial parts have been thrown away. Finding out cultivation method of Glycyrrhiza uralensis Fischer to improve chemical ingredients and biological activities has been tried these days. In this study, different wavelengths of light emitting diode (LED) were used for a cultivation of Glycyrrhiza uralensis Fischer. Antioxidant activities and inhibitory effect on mutagenecity of samples were evaluated. The stem and leave cultivated under blue light (BL-0) showed the strongest antioxidant activities of $3.02{\pm}0.13{\mu}g/ml$ ($EC_{50}$) and $2.18{\pm}0.18{\mu}g/ml$ ($EC_{50}$) in DPPH and ABTS radical scavenging test, respectively. Total phenolic content of BL-0 was $2.93{\pm}0.11g/100g$, the highest value between cultivation conditions. However, antioxidant activities of the stem and leave cultivated under red light were the weakest between samples. All of the stem and leave used in this study showed inhibitory effect on mutagenecity of 1-nitropyrene. BL-0 showed stronger inhibitory effects on mutagenicity of Trp-P-1, Trp-P-2, and AFB1 than samples cultivated under other conditions. Only on mutagenecity of 2-aminoanthracene, the stem and leave cultivated at 1 m apart from red light (RL-1) showed the strongest inhibitory effect. These results indicate that blue LED might be the most effective condition for improvement of physiological activities for the aerial parts of Glycyrrhiza uralensis Fischer in cultivation. The components were identified with GC/MS. Cytidine was detected only in RL-1 at 25 min of retention time and 2-bromotrimethylene glycol was detected only in BL-0 at 37 min.
The objective of this study was to identify the effect of zebularine soaking on the early growth stage of barley (Hordeum vulgare L.). Hence, root elongation was measured daily according to the different concentrations of zebularine (1.0, 2.5, 5.0, and 10.0 μM) for 4 days. On the first day, root length at 2.5 and 5.0 μM was significantly longer than that in the non-treated control. On the second day, root length was not significantly different among all concentrations and controls. On the third day, root elongation was suppressed by the effect of zebularine, except at 2.5 μM. The treatment time of zebularine accounted for the largest proportion of the variation in root elongation. After transplanting, plant growth velocity was similar to that of the control; however, plants at 2.5 μM showed faster growth velocity than that of the other concentrations and the control. In the metaphase of mitosis, most chromosomes of cells under zebularine treatment were ordinary regardless of the concentration, while some cells with short chromosomes were investigated at around 2%. The short chromosome showed a centromere. In addition, it showed short and long arms based on the centromere. The lengths of the short and long arms were different for each short chromosome. It is necessary to study the effect of the short chromosome as a chromosomal function on plant growth and phenotype through investigation of meiosis and fertilization at the chromosome level.
Chemotherapy is the primary therapy for malignant lymphoma (ML). However, the clinical outcome is still far from satisfactory. Consequently, an understanding of the mechanism of modulating cancer cell invasion, migration and metastasis is important for the development of more effective chemotherapeutic agents. FNC, 2'-deoxy-2'-${\beta}$-fluoro-4'-azidocytidine, a novel cytidine analogue, has demonstrated significantly inhibitory effects on proliferation of several non-Hodgkin lymphoma (NHL) cell lines. A previous study indicated that FNC effectively inhibited the growth of Raji and JeKo-1 cells in dose-time dependent effects with $IC_{50}$ values of $0.2{\mu}M$ and $0.097{\mu}M$, respectively. This study was focused on investigating the anti-invasive properties of FNC on NHL cells and its potential mechanisms of action. Cell adhesion and transwell chamber assays were utilized to investigate the anti-invasive effects of FNC on Raji and JeKo-1 cells. Real-time PCR and Western blotting were employed to qualify the expression of ${\beta}$-catenin, the glycogen synthase kinase-3 beta (GSK-$3{\beta}$), E-cadherin vascular endothelial growth factor (VEGF), matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9). The results revealed that FNC remarkably inhibited the adhesion, migration and invasion of two human aggressive non-Hodgkin lymphoma cell lines in a dose dependent manner. Furthermore, ${\beta}$-catenin, MMP-2, MMP-9, VEGF mRNA and protein levels were decreased after FNC treatment, while GSK-$3{\beta}$ and E-cadherin increased. Our studies thus provide evidence and a rationale that FNC may offer an effective chemotherapeutic agent by regulating the invasion and metastasis of aggressive non-Hodgkin lymphoma via inhibition of the Wnt/${\beta}$-catenin signaling pathway.
Ullah, Imran;Lee, Ran;Oh, Keon Bong;Hwang, Seongsoo;Kim, Youngim;Hur, Tai-Young;Ock, Sun A
Asian-Australasian Journal of Animal Sciences
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v.33
no.11
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pp.1837-1847
/
2020
Objective: To evaluate the pancreatic differentiation potential of α-1,3-galactosyltransferase knockout (GalTKO) pig-derived bone marrow-derived mesenchymal stem cells (BM-MSCs) using epigenetic modifiers with different pancreatic induction media. Methods: The BM-MSCs have been differentiated into pancreatic β-like cells by inducing the overexpression of key transcription regulatory factors or by exposure to specific soluble inducers/small molecules. In this study, we evaluated the pancreatic differentiation of GalTKO pig-derived BM-MSCs using epigenetic modifiers, 5-azacytidine (5-Aza) and valproic acid (VPA), and two types of pancreatic induction media - advanced Dulbecco's modified Eagle's medium (ADMEM)-based and N2B27-based media. GalTKO BM-MSCs were treated with pancreatic induction media and the expression of pancreas-islets-specific markers was evaluated by real-time quantitative polymerase chain reaction, Western blotting, and immunofluorescence. Morphological changes and changes in the 5'-C-phosphate-G-3' (CpG) island methylation patterns were also evaluated. Results: The expression of the pluripotent marker (POU class 5 homeobox 1 [OCT4]) was upregulated upon exposure to 5-Aza and/or VPA. GalTKO BM-MSCs showed increased expression of neurogenic differentiation 1 in the ADMEM-based (5-Aza) media, while the expression of NK6 homeobox 1 was elevated in cells induced with the N2B27-based (5-Aza) media. Moreover, the morphological transition and formation of islets-like cellular clusters were also prominent in the cells induced with the N2B27-based media with 5-Aza. The higher insulin expression revealed the augmented trans-differentiation ability of GalTKO BM-MSCs into pancreatic β-like cells in the N2B27-based media than in the ADMEM-based media. Conclusion: 5-Aza treated GalTKO BM-MSCs showed an enhanced demethylation pattern in the second CpG island of the OCT4 promoter region compared to that in the GalTKO BM-MSCs. The exposure of GalTKO pig-derived BM-MSCs to the N2B27-based microenvironment can significantly enhance their trans-differentiation ability into pancreatic β-like cells.
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